Novel activators of glucokinase

ABSTRACT

The present invention provides for novel compounds of Formulas I and II and pharmaceutically acceptable salts and co-crystals thereof which have glucokinsae activator activity. The present invention further provides for pharmaceutical compositions comprising the same as well as methods of treating, preventing, delaying the time to onset or reducing the risk for the development or progression of a disease or condition for which one or more glucokinase activator is indicated, including Type 1 and 2 diabetes, impaired glucose tolerance, insulin resistance and hyperglycemia. The present invention also provides for processes of making the compounds of Formulas I and II, including salts and co-crystals thereof, and pharmaceutical compositions comprising the same.

RELATED APPLICATIONS

This application is a continuation application of U.S. patentapplication Ser. No. 14/585,073, filed Dec. 29, 2014, which is acontinuation application of U.S. patent application Ser. No. 13/115,647,filed May 25, 2011, which is a continuation application of U.S. patentapplication Ser. No. 12/673,743, filed Aug. 13, 2008, which is a 371 ofInternational Application No. PCT/US2008/073026, filed Aug. 13, 2008,which claims priority to and the benefit of U.S. Provisional ApplicationNo. 60/955,522, filed Aug. 13, 2007, the entire contents of all of whichare incorporated herein by reference.

FIELD OF THE INVENTION

The present invention is directed towards novel activators ofglucokinase.

BRIEF SUMMARY OF THE INVENTION

The present invention relates to compounds and pharmaceuticalcompositions of Formulas I and II, including pharmaceutically acceptablesalts or co-crystals, and prodrugs thereof which activate the enzymeglucokinase. The present invention further provides for pharmaceuticalcompositions comprising the same a well as methods of treating,preventing, delaying the time to onset or reducing the risk for thedevelopment or progression of a disease or condition for which one ormore glucokinase activator is indicated, including Type 1 and 2diabetes, impaired glucose tolerance, insulin resistance andhyperglycemia. Also provided are methods of making or manufacturingcompounds of Formula I and II and pharmaceutically acceptable salts orco-crystals, and prodrugs thereof.

DETAILED DESCRIPTION OF THE INVENTION Definitions

As used herein, the following terms are defined with the followingmeanings:

“Acyl” refers to —C(O)R^(s) where R^(s) is alkyl, heterocycloalkyl, oraryl.

“Acylalkyl” refers to an alkyl-C(O)-alk-, wherein “alk” is alkylene.

“Acylamino” refers to and R^(w)C(O)—NR^(w)—, wherein R^(w) is —H, alkyl,aryl, aralkyl, and heterocycloalkyl.

“Acyloxy” refers to the ester group —O—C(O)R^(t), where R^(t) is H,alkyl, alkenyl, alkynyl, aryl, aralkyl, or heterocycloalkyl.

“Alicyclic” refers to a cyclic group or compound which combines theproperties of aliphatic and cyclic compounds and include but are notlimited to cycloalkyl and bridged cycloalkyl compounds. The cycliccompound includes heterocycles. Cyclohexenylethyl, cyclohexanylethyl,and norbornyl are suitable alicyclic groups. Such groups may beoptionally substituted.

“Alkanoyl” refers to the group alkyl-C(O)—.

“Alkenyl” refers to unsaturated groups which have 2 to 12 atoms andcontain at least one carbon-carbon double bond and includesstraight-chain, branched-chain and cyclic groups included alkenylene andalkynylene. Alkenyl groups may be optionally substituted. Suitablealkenyl groups include allyl. “1-alkenyl” refers to alkenyl groups wherethe double bond is between the first and second carbon atom. If the1-alkenyl group is attached to another group, it is attached at thefirst carbon.

“Alkylaminoalkyl-” refers to the group alkyl-NR^(u)-alk- wherein each“alk” is an independently selected alkylene, and R^(u) is H or loweralkyl. “Lower alkylaminoalkyl-” refers to groups where the alkyl and thealkylene group is lower alkyl and alkylene, respectively.

“Alkylaminoalkylcarboxy” refers to the group alkyl-NR^(u)-alk-C(O)—O—where “alk” is an alkylene group, and R^(u) is a H or lower alkyl.

“Alkylaminoaryl-” refers to the group alkyl-NR^(v)-aryl- wherein “aryl”is a divalent group and R^(v) is —H, alkyl, aralkyl, orheterocycloalkyl. In “lower alkylaminoaryl-”, the alkyl group is loweralkyl.

“Alkoxy-” or “alkyloxy-” refers to the group alkyl-O—.

“Alkoxyalkyl-” or “alkyloxyalkyl-” refers to the group alkyl-O-alk-wherein “alk” is an alkylene group. In “lower alkoxyalkyl-”, each alkyland alkylene is lower alkyl and alkylene, respectively.

“Alkoxyaryl-” refers to an aryl group substituted with an alkyloxygroup. In “lower alkyloxyaryl-”, the alkyl group is lower alkyl.

“Alkoxycarbonyloxy-” refers to alkyl-O—C(O)—O—.

“Alkyl” refers to a straight or branched chain or cyclic chainhydrocarbon radical with only single carbon-carbon bonds. Representativeexamples include methyl, ethyl, propyl, isopropyl, cyclopropyl, butyl,isobutyl, tert-butyl, cyclobutyl, pentyl, cyclopentyl, hexyl, andcyclohexyl, all of which may be optionally substituted. Alkyl groups areC₁-C₁₂.

“Alkylaryl-” refers to an aryl group substituted with an alkyl group.“Lower alkylaryl-” refers to such groups where alkyl is lower alkyl.

“Alkylene” refers to a divalent straight chain, branched chain or cyclicsaturated aliphatic group. In one aspect the alkylene group contains upto and including 10 atoms. In another aspect the alkylene chain containsup to and including 6 atoms. In a further aspect the alkylene groupscontains up to and including 4 atoms. The alkylene group can be eitherstraight, branched chain or cyclic.

“Alkylthio-” and “alkylthio-” refer to the group alkyl-S—.

“Alkylthioalkyl-” refers to the group alkyl-S-alk- wherein “alk” is analkylene group. In “lower alkylthioalkyl-” each alkyl and alkylene islower alkyl and alkylene, respectively.

“Alkylthiocarbonyloxy-” refers to alkyl-S—C(O)—O—.

“Alkynyl” refers to unsaturated groups which have 2 to 12 atoms andcontain at least one carbon-carbon triple bond and includesstraight-chain, branched-chain and cyclic groups. Alkynyl groups may beoptionally substituted. Suitable alkynyl groups include ethynyl.“1-alkynyl” refers to alkynyl groups where the triple bond is betweenthe first and second carbon atom. If the 1-alkynyl group is attached toanother group, e.g., it is a W substituent attached to the cyclicphosphonate, it is attached at the first carbon.

“Amido” refers to the NR^(w) ₂ group next to an acyl or sulfonyl groupas in NR^(w) ₂—C(O)—, R^(w)C(O)—NR^(w)—, NR^(w) ₂—S(═O)₂— andR^(w)S(═O)₂—NR^(w)—, wherein each R^(w) independently includes —H,alkyl, aryl, aralkyl, and heterocycloalkyl.

“Amino” refers to —NR^(x)R^(x) wherein each R^(x) is independentlyselected from hydrogen, alkyl, aryl, aralkyl and heterocycloalkyl, allexcept H are optionally substituted, or wherein both R^(x) together forma cyclic ring system.

“Aminoalkyl” refers to the group NR^(t) ₂-alk- wherein “alk” is analkylene group and R^(t) is selected from —H, alkyl, aryl, aralkyl, andheterocycloalkyl.

“Aminocarboxamidoalkyl” refers to the group NR^(y) ₂—C(O)—N(R^(y))-alk-wherein each R^(y) is independently an alkyl group or H and “alk” is analkylene group. “Lower aminocarboxamidoalkyl-” refers to such groupswherein “alk” is lower alkylene.

“Animal” includes birds and mammals, in one embodiment a mammal,including rodents, livestock, companion animals/pets or humans of eithergender.

“Aralkyl” refers to an alkylene group substituted with an aryl group.Suitable aralkyl groups include benzyl, picolyl, and the like, and maybe optionally substituted.

“Aralkyloxyalkyl-” refers to the group aryl-alk-O-alk- wherein “alk” isan alkylene group. “Lower aralkyloxyalkyl-” refers to such groups wherethe alkylene groups are lower alkylene.

“Aroyl” refers to the group aryl-C(O)—.

“Aryl” refers to aromatic groups which have 5-14 ring atoms and at leastone ring having a conjugated pi electron system and includes carbocyclicaryl, heterocyclic aryl, bicyclic aryl (e.g., naphthyl) and biarylgroups (e.g., biphenyl), all of which may be optionally substituted.

“Arylamino” refers to the group aryl-NH—

“Aralkylamino” refers to the group —N-alk-aryl wherein “alk” isalkylene.

“Arylene” refers to divalent aromatic ring systems which have 5-14 atomsand at least one ring having a conjugated pi electron system andincludes carbocyclic arylene, heterocyclic arylene and biarylene groups,all of which may be optionally substituted.

“Arylaminoalkyl-” refers to the group aryl-N(R^(w))-alk- wherein “alk”is an alkylene group and R^(w) is —H, alkyl, aryl, aralkyl, orheterocycloalkyl. In “lower arylaminoalkyl-”, the alkylene group islower alkylene.

“Aryloxy” refers to aryl-O—.

“Aryloxyalkyl-” refers to an alkyl group substituted with an aryloxygroup.

“Aryloxycarbonyl” refers to the group aryl-O—C(O)—O—.

“Aryloxycarbonyloxy-” refers to aryl-O—C(O)—O—.

“Atherosclerosis” refers to a condition characterized by irregularlydistributed lipid deposits in the intima of large and medium-sizedarteries wherein such deposits provoke fibrosis and calcification.

“Biaryl” represents aryl groups which have 5-14 atoms containing morethan one aromatic ring including both fused ring systems and aryl groupssubstituted with other aryl groups. Such groups may be optionallysubstituted. Suitable biaryl groups include naphthyl and biphenyl.

“Binding” means the specific association of the compound of interest tothe target of interest, e.g., a receptor.

“C₂₋₆-perfluoroalkyl” refers to a 2 to 6 carbon alkyl group where all ofthe carbon atoms are exhaustively substituted with fluorine. Nonlimiting examples include trifluoromethyl, pentafluoroethyl,heptafluoropropyl, pentafluorocyclopropyl, and the like.

“C₄₋₈-cycloalkenyl” refers to a non-aromatic, carbocyclic group having 4to 8 carbon atoms and containing at least one double bond.

“C₃₋₈-cycloalkyloxy” refers to —O—C₃₋₈-cycloalkyl where C₃₋₈-cycloalkylis an aliphatic carbocyclic group having 3 to 8 carbon atoms.

“C₃₋₈-cycloalkylthio” refers to —S—C₃₋₈-cycloalkyl where C₃₋₈-cycloalkylis a 3 to 8 aliphatic carbocyclic group having 3 to 8 carbon atoms

“Carboxylamido” or “carboxamido” refer to NR^(w) ₂—C(O)—, wherein eachR^(w) include —H, alkyl, aryl, aralkyl, and heterocycloalkyl.

“Carboxamidoalkylaryl” refers to NR^(w) ₂—C(O)-alk-aryl-, where R^(w)includes H, alkyl, aryl, aralkyl, and heterocycloalkyl.

“Carboxamidoaryl” refers to NR^(w)—C(O)-aryl- wherein “alk” is alkyleneand R^(w) include H, alkyl, aryl, aralkyl, and heterocycloalkyl.

“Carbocyclic aryl” groups are groups which have 6-14 ring atoms whereinthe ring atoms on the aromatic ring are carbon atoms, and includemonocyclic carbocyclic aryl groups and polycyclic or fused compoundssuch as optionally substituted naphthyl groups.

“Carboxy esters” refers to —C(O)OR^(z) where R^(z) is alkyl, aryl,aralkyl, cyclic alkyl, or heterocycloalkyl, each optionally substituted.

“Carboxyl” refers to —C(O)OH.

“Cyano” refers to —C≡N.

“Cyclic alkyl” or “cycloalkyl” refers to alkyl groups that are cyclic of3 to 10 carbon atoms, and, in one aspect, are 3 to 6 carbon atoms. Thecycloalkyl groups include fused cyclic, bridged cyclic and spirocyclicgroups. Examples of cyclic alkyl groups include but are not limited tocyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, decalin,bicycle[3.1.1]heptane, bycyclo[2.2.1]heptane, bycyclo[2.2.2]octane,bicycle[3.2.2]nonane, spiro[2.5]octane, spiro[3.5]nonane, adamantyl andthe like. Such groups may be substituted.

“Cycloalkyloxy” refers to the group cycloalkyl-O—.

“Cycloalkylalkoxy” refers to the group cycloalkyl-alkyl-O—.

“Co-crystal” as used herein means a crystalline material comprised oftwo or more unique solids at room temperature that are H-bonded.

“Diabetes” refers to a heterogeneous group of disorders that shareimpaired glucose intolerance, hyperglycemia, and/or insulin resistancein common. Type I diabetes is characterized by pancreatic endocrineinsufficiency or absence; and type II is characterized by insulinresistance. Diabetes refers to disorders in which carbohydrateutilization is reduced; and may be characterized by hyperglycemia,glycosuria, ketoacidosis, neuropathy or nephropathy, increased hepaticglucose production, insulin resistance in various tissues, insufficientinsulin secretion and enhanced or poorly controlled glucagon secretionfrom the pancreas.

Several pathogenic processes are involved in the development ofdiabetes. These range from autoimmune destruction of the beta-cells ofthe pancreas with consequent insulin deficiency to abnormalities thatresult in resistance to insulin action. The basis of the abnormalitiesin carbohydrate, fat, and protein metabolism in diabetes is deficientaction of insulin on target tissues. Deficient insulin action resultsfrom inadequate insulin secretion and/or diminished tissue responses toinsulin at one or more points in the complex pathways of hormone action.Impairment of insulin secretion and defects in insulin action frequentlycoexist in the same patient.

Symptoms of marked hyperglycemia include polyuria, polydipsia, weightloss, sometimes with polyphagia, and blurred vision. The vast majorityof cases of diabetes fall into two broad etiopathogenetic categories. Inone category, type 1 diabetes, the cause is an absolute deficiency ofinsulin secretion. Individuals at increased risk of developing this typeof diabetes can often be identified by scrological evidence of anautoimmune pathologic process occurring in the pancreatic islets and bygenetic markers. In the other, much more prevalent category, type 2diabetes, the cause is a combination of resistance to insulin action andan inadequate compensatory insulin secretory response. In the lattercategory, a degree of hyperglycemia sufficient to cause pathologic andfunctional changes in various target tissues, but without clinicalsymptoms, may be present for a long period of time before diabetes isdetected. During this asymptomatic period, it is possible to demonstratean abnormality in carbohydrate metabolism by measurement of plasmaglucose in the fasting state or after a challenge with an oral glucoseload.

Criteria for the diagnosis of diabetes include:

1. Symptoms of diabetes plus casual plasma glucose concentration 200mg/dl (11.1 mmol/l). Casual is defined as any time of day without regardto time since last meal. The classic symptoms of diabetes includepolyuria, polydipsia, and unexplained weight loss; or2. Fasting Plasma Glucose equal to or greater than 126 mg/dl (7.0mmol/1). Fasting is defined as no caloric intake for at least 8 h; or3. 2-h post-meal or post oral glucose tolerance test (OGTT) glucoseconcentration of 200 mg/dl (11.1 mmol/l) during an OGTT. The test can beperformed as described by WHO, using a glucose load containing theequivalent of 75 g anhydrous glucose dissolved in water.

“Energy expenditure” means basal or resting metabolic rate as defined bySchoeller et al., J Appl Physiol.; 53(4):955-9 (1982). Increases in theresting metabolic rate can be also be measured using increases in O₂consumption and/or CO₂ efflux and/or increases in organ or bodytemperature.

“Enhanced oral bioavailability” refers to an increase of at least 50% ofthe absorption of the dose of the parent drug, unless otherwisespecified. In an additional aspect the increase in oral bioavailabilityof the prodrug (compared to the parent drug) is at least 100% (at leasta doubling of the absorption). Measurement of oral bioavailabilityusually refers to measurements of the prodrug, drug, or drug metabolitein blood, plasma, tissues, or urine following oral administrationcompared to measurements following systemic administration of thecompound administered orally.

“Enhancing” refers to increasing or improving a specific property.

“Haloalkyl” refers to an alkyl group substituted with one halo (halogengroup).

“Halogen” or “halo” refers to —F, —Cl, —Br and —I.

“Heteroalicyclic” refers to an alicyclic group or compound having 1 to 4heteroatoms selected from nitrogen, sulfur, phosphorus and oxygen.

“Heteroarylalkyl” refers to an alkylene group substituted with aheteroaryl group.

“Heteroarylene” refers to a divalent, aromatic, heterocyclic ringcontaining 5-14 ring atoms wherein 1 to 4 heteroatoms in the aromaticring are ring atoms and the remainder of the ring atoms being carbonatoms.

Alternative: “Heteroarylene” refers to a divalent heterocyclic aryl orheteroaryl group.

“Heterocyclic” or “heterocyclyl” refer to cyclic groups of 3 to 10 atomsor cyclic groups of 3 to 6 atoms. These groups contain at least oneheteroatom, and in some aspects contain 1 to 3 heteroatoms. Suitableheteroatoms include oxygen, sulfur, and nitrogen. Heterocyclic groupsmay be attached through a nitrogen or carbon atom in the ring.Heterocyclic and heterocyclyl cyclic groups include, e.g., heterocyclicalkyl or heterocycloalkyl groups. The heterocyclic alkyl groups includeunsaturated cyclic, fused cyclic and spirocyclic groups. Suitableheterocyclic groups include pyrrolidinyl, morpholino, morpholinoethyl,and pyridyl.

“Heterocyclic aryl” or “heteroaryl groups” are groups which have 5-14ring atoms wherein 1 to 4 heteroatoms are ring atoms in the aromaticring and the remainder of the ring atoms being carbon atoms. Suitableheteroatoms include oxygen, sulfur, nitrogen, and selenium. Suitableheteroaryl groups include furanyl, thienyl, pyridyl, pyrrolyl, N-loweralkyl pyrrolyl, pyridyl-N-oxide, pyrimidyl, pyrazinyl, imidazolyl,benzimidazolyl, benzofuranyl, benzothiophenyl, and the like, alloptionally substituted.

“Hydroxyalkyl” refers to an alkyl group substituted with one —OH.

“Hypercholesterolemia” refers to presence of an abnormally large amountof cholesterol in the cells and plasma of the circulating blood.

“Hyperinsulinemia” refers to a patient with a fasting serum insulinconcentration of at least 12 μU/mL.

“Hyperlipidemia” or “lipemia” refers to the presence of an abnormallylarge amount of lipids in the circulating blood.

“Insulin resistance” is defined clinically as the impaired ability of aknown quantity of exogenous or endogenous insulin to increase whole bodyglucose uptake and utilization.

“Impaired glucose tolerance (IGT)” refers to a condition known toprecede the development of overt Type 2 diabetes. It is characterized byabnormal blood glucose excursions following a meal. The current criteriafor the diagnosis of IGT are based on 2-h plasma glucose levels post a75 g oral glucose test (144-199 mg/dL). Although variable frompopulation to population studied, IGT progresses to full-blown NIDDM ata rate of 1.5 to 7.3% per year, with a mean of 3-4% per year.Individuals with IGT are believed to have a 6 to 10-fold increased riskin developing Type 2 diabetes. IGT is an independent risk factor for thedevelopment of cardiovascular disease.

“Increased or enhanced liver specificity” refers to an increase in theliver specificity ratio in animals treated with a compound of thepresent invention and a control compound.

“Lower” referred to herein in connection with organic radicals orcompounds respectively defines such radicals or compounds as containingup to and including 10 carbon atoms. One aspect of this inventionprovides organic radicals or compounds as containing up to and including6 carbon atoms. Yet another aspect of the invention provides organicradicals or compounds that contain one to four carbon atoms. Such groupsmay be straight chain, branched, or cyclic.

“Liver specificity” refers to the ratio:

$\frac{\left\lbrack {{drug}\mspace{14mu} {or}\mspace{14mu} a\mspace{14mu} {drug}\mspace{14mu} {metabolite}\mspace{14mu} {in}\mspace{14mu} {liver}\mspace{14mu} {tissue}} \right\rbrack}{\left\lbrack {{drug}\mspace{14mu} {or}\mspace{14mu} a\mspace{14mu} {drug}\mspace{14mu} {metabolite}{\mspace{11mu} \;}{in}\mspace{14mu} {blood}\mspace{14mu} {or}\mspace{14mu} {another}\mspace{14mu} {issue}} \right\rbrack}$

as measured in animals treated with the drug or a prodrug. The ratio canbe determined by measuring tissue levels at a specific time or mayrepresent an AUC based on values measured at three or more time points.

“Metabolic disease” includes diseases and conditions such as obesity,diabetes and lipid disorders such as hypercholesterolemia,hyperlipidemia, hypertriglyceridemia as well as disorders that areassociated with abnormal levels of lipoproteins, lipids, carbohydratesand insulin such as metabolic syndrome X, diabetes, impaired glucosetolerance, atherosclerosis, coronary artery disease, cardiovasculardisease, polycystic ovary syndrome (PCOS).

“Metabolic Syndrome” or “Metabolic Syndrome X” refers to a conditionidentified by the presence of three or more of these components:

-   -   Central obesity as measured by waist circumference:        -   Men: Greater than 40 inches        -   Women: Greater than 35 inches    -   Fasting blood triglycerides greater than or equal to 150 mg/dL    -   Blood HDL cholesterol:        -   Men: Less than 40 mg/dL        -   Women: Less than 50 mg/dL    -   Blood pressure greater than or equal to 130/85 mmHg    -   Fasting blood glucose greater than or equal to 110 mg/dL

“Nitro” refers to —NO₂.

“Obesity” refers to the condition of being obese. Being obese is definedas a BMI of 30.0 or greater; and extreme obesity is defined at a BMI of40 or greater. “Overweight” is defined as a body mass index of 25.0 to29.9.

“Oxo” refers to ═O in an alkyl or heterocycloalkyl group.

“Perhalo” refers to groups wherein every C—H bond has been replaced witha C-halo bond on an aliphatic or aryl group. Non-linking examples ofperhaloalkyl groups include —CF₃ and —CFCl₂.

“Pharmaceutically acceptable salt” includes salts of compounds of theinvention derived from the combination of a compound of this inventionand an organic or inorganic acid or base. Suitable acids include aceticacid, adipic acid, benzenesulfonic acid,(+)-7,7-dimethyl-2-oxobicyclo[2.2.1]heptane-1-methanesulfonic acid,citric acid, 1,2-ethanedisulfonic acid, dodecyl sulfonic acid, fumaricacid, glucoheptonic acid, gluconic acid, glucuronic acid, hippuric acid,hydrochloride hemiethanolic acid, HBr, HCl, HI, 2-hydroxyethanesulfonicacid, lactic acid, lactobionic acid, maleic acid, methanesulfonic acid,methylbromide acid, methyl sulfuric acid, 2-naphthalenesulfonic acid,nitric acid, oleic acid, 4,4′-methylenebis[3-hydroxy-2-naphthalenecarboxylic acid], phosphoric acid,polygalacturonic acid, stearic acid, succinic acid, sulfuric acid,sulfosalicylic acid, tannic acid, tartaric acid, terphthalic acid, andp-toluenesulfonic acid.

“Patient” means an animal.

“Preventing” includes a slowing of the progress or development of adisease before onset or precluding onset of a disease.

“Prodrug” as used herein refers to any compound that when administeredto a biological system generates a biologically active compound as aresult of spontaneous chemical reaction(s), enzyme catalyzed chemicalreaction(s), and/or metabolic chemical reaction(s), or a combination ofeach. Standard prodrugs are formed using groups attached tofunctionality, e.g., HO—, HS—, HOOC—, .NHR, associated with the drug,that cleave in vivo. Standard prodrugs include but are not limited tocarboxylate esters where the group is alkyl, aryl, aralkyl,acyloxyalkyl, alkoxycarbonyloxyalkyl as well as esters of hydroxyl,thiol and amines where the group attached is an acyl group, analkoxycarbonyl, aminocarbonyl, phosphate or sulfate. The groupsillustrated are exemplary, not exhaustive, and one skilled in the artcould prepare other known varieties of prodrugs. Such prodrugs of thecompounds of the invention, fall within this scope. Prodrugs mustundergo some form of a chemical transformation to produce the compoundthat is biologically active or is a precursor of the biologically activecompound. In some cases, the prodrug is biologically active, usuallyless than the drug itself, and serves to improve drug efficacy or safetythrough improved oral bioavailability, and/or pharmacodynamic half-life,etc. Prodrug forms of compounds may be utilized, for example, to improvebioavailability, improve subject acceptability such as by masking orreducing unpleasant characteristics such as bitter taste orgastrointestinal irritability, alter solubility such as for intravenoususe, provide for prolonged or sustained release or delivery, improveease of formulation, or provide site-specific delivery of the compound.Prodrugs are described in The Organic Chemistry of Drug Design and DrugAction, by Richard B. Silverman, Academic Press, San Diego, 1992.Chapter 8: “Prodrugs and Drug delivery Systems” pp. 352-401; Design ofProdrugs, edited by H. Bundgaard, Elsevier Science, Amsterdam, 1985;Design of Biopharmaceutical Properties through Prodrugs and Analogs, Ed.by E. B. Roche, American Pharmaceutical Association, Washington, 1977;and Drug Delivery Systems, ed. by R. L. Juliano, Oxford Univ. Press,Oxford, 1980.

“Significant” or “statistically significant” means a result (i.e.experimental assay result) where the p-value is =0.05 (i.e. the chanceof a type I error is less than 5%) as determined by an art-acceptedmeasure of statistical significance appropriate to the experimentaldesign.

“Substituted” or “optionally substituted” includes groups substituted byone to six substituents, independently selected from lower alkyl, loweraryl, lower aralkyl, lower cyclic alkyl, lower heterocycloalkyl,hydroxy, lower alkoxy, lower aryloxy, perhaloalkoxy, aralkoxy, lowerheteroaryl, lower heteroaryloxy, lower heteroarylalkyl, lowerheteroaralkoxy, azido, amino, halo, lower alkylthio, oxo, loweracylalkyl, lower carboxy esters, carboxyl, -carboxamido, nitro, loweracyloxy, lower aminoalkyl, lower alkylaminoaryl, lower alkylaryl, loweralkylaminoalkyl, lower alkoxyaryl, lower arylamino, lower aralkylamino,sulfonyl, lower-carboxamidoalkylaryl, lower-carboxamidoaryl, lowerhydroxyalkyl, lower haloalkyl, lower alkylaminoalkylcarboxy-, loweraminocarboxamidoalkyl-, cyano, lower alkoxyalkyl, lower perhaloalkyl,and lower arylalkyloxyalkyl. The phrase “optionally substituted” can bereplaced by the phrase “substituted or unsubstituted” throughout thisapplication.

“Substituted aryl” and “substituted heteroaryl” refers to aryl andheteroaryl groups substituted with 1-3 substituents. These substituentsare selected from the group consisting of lower alkyl, lower alkoxy,lower perhaloalkyl, halo, hydroxy, and amino.

“Sulphon(yl)amido” or “sulfon(yl)amido” refer to NR^(w) ₂—S(═O)₂— andR^(w)S(═O)₂—NR^(w)—, wherein each R^(w) independently include alkyl,aryl, aralkyl, and heterocycloalkyl.

“Sulfonamidoalkylaryl” and “sulfonamidoaryl” refers to anaryl-alk-NR^(w)—S(═O)₂—, and ar-NR^(w)—S(═O)—, respectively where “ar”is aryl, “alk” is alkylene, R^(w) includes —H, alkyl, aryl, aralkyl, andheterocycloalkyl.

“Sulphonate” or “sulfonate” refers to —SO₂OR^(w), where R^(w) is —H,alkyl, aryl, aralkyl, or heterocycloalkyl.

“Sulphonyl” or “sulfonyl” refers to —SO₂R^(w), where R^(w) is alkyl,aryl, aralkyl, or heterocycloalkyl.

“Therapeutically effective amount” means an amount of a compound or acombination of compounds that ameliorates, attenuates or climinates oneor more of the symptoms of a particular disease or condition orprevents, modifies, or delays the onset of one or more of the symptomsof a particular disease or condition.

“Treating” or “treatment” of a disease includes a slowing of theprogress or development of a disease after onset or actually reversingsome or all of the disease affects. Treatment also includes palliativetreatment.

“Type 1 diabetes” (formerly known as “childhood.” “juvenile,”“insulin-dependent” diabetes) is a form of diabetes characterized by anabsolute deficiency of insulin secretion. Individuals at increased riskof developing this type of diabetes can often be identified byserological evidence of an autoimmune pathologic process occurring inthe pancreatic islets and by genetic markers. Type 1 diabetes may becaused by immune mediated beta-cell destruction, usually leading toabsolute insulin deficiency or may be idiopathic, having no knownetiologies.

“Type 2 diabetes” refers to a heterogeneous disorder characterized byimpaired insulin secretion by the pancreas and insulin resistance intissues such as the liver, muscle and adipose tissue. The manifestationsof the disease include one or more of the following: impaired glucosetolerance, fasting hyperglycemia, glycosuria, decreased levels ofinsulin, increased levels of glucagon, increased hepatic glucose output,reduced hepatic glucose uptake and glycogen storage, reduced whole bodyglucose uptake and utilization, dyslipidemia, fatty liver, ketoacidosis,microvascular diseases such as retinopathy, nephropathy and neuropathy,and macrovascular diseases such as coronary heart disease.

“Phosphonate, phosphonic acid monoester and phosphinate prodrug” refersto compounds that break down chemically or enzymatically to a phosphonicacid or phosphine acid group in vivo. As employed herein the termincludes, but is not limited to, the following groups and combinationsof these groups:

Acyloxyalkyl esters which are well described in the literature (Farquharet al., J. Pharm. Sci., 72: 324-325 (1983)).

Other acyloxyalkyl esters are possible in which a cyclic alkyl ring isformed. These esters have been shown to generate phosphorus-containingnucleotides inside cells through a postulated sequence of reactionsbeginning with deesterification and followed by a series of eliminationreactions (e.g., Freed et al., Biochem. Pharm., 38: 3193-3198 (1989)).

Another class of these double esters known as alkyloxycarbonyloxymethylesters, as shown in formula A, where R^(a) is alkoxy, aryloxy,alkylthio, arylthio, alkylamino, or arylamino; each R^(e) isindependently —H, alkyl, aryl, alkylaryl, or heterocycloalkyl have beenstudied in the area of β-lactam antibiotics (Nishimura at al., J.Antibiotics, 40(1): 81-90 (1987); for a review see Ferres, H., Drugs ofToday, 19: 499 (1983)). More recently Cathy, M. S., et al. (Abstractfrom AAPS Western Regional Meeting, April, 1997) showed that thesealkyloxycarbonyloxymethyl ester prodrugs on(9-[(R)-2-phosphonomethoxy)propyl]adenine (PMPA) are bioavailable up to30% in dogs.

wherein R^(a) and R^(c) are independently H, alkyl, aryl, alkylaryl, andalicyclic; (see WO 90/08155; WO 90/10636) and R^(b), for e.g., isselected from —OH, —CH₃, —H, —O—CH₃ or monoester prodrug moiety.

Other acyloxyalkyl esters are possible in which a cyclic alkyl ring isformed such as shown in formula B. These esters have been shown togenerate phosphorus-containing nucleotides inside cells through apostulated sequence of reactions beginning with deesterification andfollowed by a series of elimination reactions (e.g., Freed et al.,Biochem. Pharm., 38: 3193-3198 (1989)).

wherein R^(d) is —H, alkyl, aryl, alkylaryl, alkoxy, aryloxy, alkylthio,arylthio, alkylamino, arylamino, or cycloalkyl.

Aryl esters have also been used as phosphonate prodrugs (e.g., DeLambertet al., J. Med. Chem. 37(7): 498-511 (1994); Serafinowska et al., J.Med. Chem. 38(8): 1372-9 (1995). Phenyl as well as mono andpoly-substituted phenyl proesters have generated the parent phosphonioacid in studies conducted in animals and in man (Formula C). Anotherapproach has been described where R^(e) is a carboxylic ester ortho tothe phosphate (Khamnei et al., J. Med. Chem. 39: 4109-15 (1996)).

wherein R^(e) is —H, alkyl, aryl, alkylaryl, alkoxy, acyloxy, halogen,amino, alkoxycarbonyl, hydroxy, cyano, or heterocycloalkyl and R^(b) isselected, for e.g., from —OH, —CH₃, —H, —O—CH₃ or monoester prodrugmoiety.

Benzyl esters have also been reported to generate the parent phosphonicacid. In some cases, using substituents at the para-position canaccelerate the hydrolysis. Benzyl analogs with 4-acyloxy or 4-alkyloxygroup [Formula D, X=—H, OR or O(CO)R or O(CO)OR] can generate the4-hydroxy compound more readily through the action of enzymes, e.g.,oxidases, esterases, etc. Examples of this class of prodrugs aredescribed in Mitchell et al., J. Chem. Soc. Perkin Trans. 12345 (1992);WO 91/19721.

wherein R^(f) and R^(g) are independently —H, alkyl, aryl, alkylaryl,alkoxy, acyloxy,

hydroxy, cyano, nitro, perhaloalkyl, halo, or alkyloxycarbonyl; R^(b) isselected, for e.g., from —OH, —CH₃, —H, —O—CH₃ or monoester prodrugmoiety, as described therein.

R^(h) and R^(i) are independently —H, alkyl, aryl, alkylaryl, halogen,or cyclic alkyl.

Thio-containing phosphonate proesters may also be useful in the deliveryof drugs to hepatocytes. These proesters contain a protected thioethylmoiety as shown in formula E. One or more of the oxygens of thephosphonate can be esterified. Since the mechanism that results inde-esterification requires the generation of a free thiolate, a varietyof thiol protecting groups are possible. For example, the disulfide isreduced by a reductase-mediated process (Puech et al., Antiviral Res.22: 155-174 (1993)). Thioesters will also generate free thiolates afteresterase-mediated hydrolysis Benzaria, et al., J. Med. Chem., 39(25):4958-65 (1996)). Cyclic analogs are also possible and were shown toliberate phosphonate in isolated rat hepatocytes. The cyclic disulfideshown below has not been previously described and is novel.

wherein R^(j) is alkylcarbonyl, alkoxycarbonyl, arylcarbonyl,aryloxycarbonyl, or alkylthio and R^(b) is selected, for e.g., from —OH,—CH, —H, —O—CH₃ or monoester prodrug moiety.

Other examples of suitable prodrugs include proester classes exemplifiedby Biller and Magnin (U.S. Pat. No. 5,157,027); Serafinowska et al., J.Med. Chem. 38(8): 1372-9 (1995); Starrett et al., J. Med. Chem, 37: 1857(1994); Martin et al. J. Pharm. Sci. 76: 180 (1987); Alexander et al,Collect. Czech. Chem. Commun, 59: 1853 (1994); and EP 0 632 048 A1. Someof the structural classes described are optionally substituted,including fused lactones attached at the omega position (formulae E4 andE5) and optionally substituted 2-oxo-1,3-dioxolenes attached through amethylene to the phosphorus oxygen (formula E6) such as:

wherein R^(m) is —H, alkyl, cycloalkyl, or heterocycloalkyl; R^(b) isselected, for e.g., from —OH, —CH₃, —H, —O—C₃ or monoester prodrugmoiety and R^(k) is —H, alkyl, aryl, alkylaryl, cyano, alkoxy, acyloxy,halogen, amino, heterocycloalkyl, or alkoxycarbonyl.

The prodrugs of Formula E6 are an example of “optionally substitutedheterocycloalkyl where the cyclic moiety contains a carbonate orthiocarbonate.”

Propyl phosphonate proesters can also be used to deliver drugs intohepatocytes. These proesters may contain a hydroxyl and hydroxyl groupderivatives at the 3-position of the propyl group as shown in formulaF2. The R^(n) and R^(p) groups can form a cyclic ring system as shown informula F2. One or more of the oxygens of the phosphonate can beesterified.

wherein R^(n) is alkyl, aryl, or heteroaryl;

R^(p) is alkylcarbonyloxy, or alkyloxycarbonyloxy;

R^(b) is selected, for e.g., from —OH, —CH₃, —H, —O—CH₃ or monoesterprodrug moiety; and

R^(q) is alkyl, aryl, heteroaryl, alkoxy, alkylamino, alkylthio,halogen,

hydrogen, hydroxy, acyloxy, or amino.

Phosphoramidate derivatives have been explored as phosphate prodrugs(e.g., McGuigan et al., J. Med. Chem., 42: 393 (1999) and referencescited therein) as shown in Formula G and H, wherein R^(r), for example,is lower alkyl, lower aryl, lower aralkyl, and as described therein.

Cyclic phosphoramidates have also been studied as phosphonate prodrugsbecause of their speculated higher stability compared to non-cyclicphosphoramidates (e.g., Starrett et al, J. Med. Chem., 37: 1857 (1994)).

Another type of phosphoramidate prodrug was reported as the combinationof S-acyl-2-thioethyl ester and phosphoramidate (Egron et al.,Nucleosides & Nucleotides, 18, 981 (1999)) as shown in Formula J whereinR^(c) is alkoxy, aryloxy, alkylthio, arylthio, alkylamino, or arylaminoand R^(a) is —H, alkyl, aryl, alkylaryl, or heterocycloalkyl:

Other prodrugs are possible based on literature reports such assubstituted ethyls for example, bis(trichloroethyl)esters as disclosedby McGuigan, et al., Bioorg Med. Chem. Lett., 3:1207-1210 (1993), andthe phenyl and benzyl combined nucleotide esters reported by Meier, C.et al., Bioorg. Med. Chem. Lett. 7:99-104 (1997).

The structure of formula L has a plane of symmetry running through thephosphorus-oxygen double bond when both R⁶⁰s are the same, V═W, and Vand W (defined herein) are either both pointing up or both pointingdown. The same is true of structures where both—NR⁶⁰s are replaced with—O—.

The term “cyclic phosphonate ester of 1,3-propane diol”, “cyclicphosphonate diester of 1,3-propane diol”, “2 oxo 2λ⁵ [1,3,2]dioxaphosphonane”, “2 oxo [1,3,2]dioxaphosphonane”, “dioxaphosphonane”refers to the following:

The phrase “together V and Z are connected via an additional 3-5 atomsto form a cyclic group containing 5-7 atoms, optionally containing 1heteroatom, substituted with hydroxy, acyloxy, alkylthiocarbonyloxy,alkoxycarbonyloxy, or aryloxycarbonyloxy attached to a carbon atom thatis three atoms from both Y groups attached to the phosphorus” includesthe following:

The structure shown above (left) has an additional 3 carbon atoms thatforms a five member cyclic group. Such cyclic groups must possess thelisted substitution to be oxidized.

The phrase “together V and Z are connected via an additional 3-5 atomsto form a cyclic group, optionally containing one heteroatom, that isfused to an aryl group attached at the beta and gamma position to the Gattached to the phosphorus” includes the following:

The phrase “together V and W are connected via an additional 3 carbonatoms to form an optionally substituted cyclic group containing 6 carbonatoms and substituted with one substituent selected from the groupconsisting of hydroxy, acyloxy, alkoxycarbonyloxy, alkylthiocarbonyloxy,and aryloxycarbonyloxy, attached to one of said additional carbon atomsthat is three atoms from a Y attached to the phosphorus” includes thefollowing:

The structure above has an acyloxy substituent that is three carbonatoms from a Y, and an optional substituent, —CH₃, on the new 6-memberedring. There has to be at least one hydrogen at each of the followingpositions: the carbon attached to Z; both carbons alpha to the carbonlabeled “3”; and the carbon attached to “OC(O)CH₃” above.

The phrase “together W and W′ are connected via an additional 2-5 atomsto form a cyclic group, optionally containing 0-2 heteroatoms, and Vmust be aryl, substituted aryl, heteroaryl, or substituted heteroaryl”includes the following:

The structure above has V=aryl, and a spiro-fused cyclopropyl group forW and W′.

The term “cyclic phosphon(amid)ate” refers to:

wherein Y is independently —O— or —NR⁶⁰—. The carbon attached to V musthave a C—H bond. The carbon attached to Z must also have a C—H bond.

For cyclic 1,3-propanyl phosphonate prodrugs of compounds of the presentinvention the term “cis” stereochemistry refers to the spatialrelationship of the V group and the carbon attached to the phosphorusatom on the six-membered ring. The formula below shows a cisstereochemistry.

The term “trans” stereochemistry for the same moiety refers to thespatial relationship of the V group and the carbon, attached to thephosphorus atom, on the six-membered ring. The formula below shows atrans-stereochemistry.

The formula below shows another trans-stereochemistry of the samemoiety.

The terms “S-configuration”, “S-isomer” and “S-prodrug” of the samerefers to the absolute configuration S of carbon C′. The formula belowshows the S-stereochemistry.

The terms “R-configuration”, “R-isomer” and “R-prodrug” of the samerefers to the absolute configuration R of carbon C′. The formula belowshows the R-stereochemistry.

The term “percent enantiomeric excess (% ee)” refers to optical purity.It is obtained by using the following formula

${\frac{\lbrack R\rbrack - \lbrack S\rbrack}{\lbrack R\rbrack + \lbrack S\rbrack} \times 100} = {{\% \mspace{14mu} R} - {\% \mspace{14mu} S}}$

where [R] is the amount of the R isomer and [S] is the amount of the Sisomer. This formula provides the % ee when R is the dominant isomer.

The term “enantioenriched” or “enantiomerically enriched” refers to asample of a chiral compound that consists of more of one enantiomer thanthe other. The extent to which a sample is enantiomerically enriched isquantitated by the enantiomeric ratio or the enantiomeric excess.

Compounds and Uses Thereof:

The enzyme glucokinase plays a critical role in the regulation of bloodglucose levels. It is expressed in a restricted number of cell types,most notably the pancreatic beta-cell and liver parenchymal cells.Glucokinase catalyzes the rate-limiting step in glucose uptake,metabolism (glycolysis), and glucose storage (glycogenesis) in cells. Inpancreatic beta cells, glucose uptake and metabolism trigger insulinsecretion. Glucokinase is often referred to as a “glucose sensor” sinceit matches the rate of insulin secretion by pancreatic beta cells aswell as the rate of glucose metabolism by liver cells to the ambientglucose concentrations.

Recent clinical data on pharmacological agents that simultaneouslyactivate glucokinase in the pancreas and the liver have revealed a highrate of the undesirable side effect of hypoglycemia in treated patients.Development of this potentially lethal condition is attributed to thepotent stimulation of insulin secretion. Compounds of the currentinvention were designed to safely lower blood glucose by selectivelytargeting glucokinase expressed in liver and thereby avoiding theactivation of glucokinase in the pancreas. Treatment of diabetic rodentswith compounds of the current invention resulted in significant bloodglucose lowering without an increase in insulin secretion. Importantly,treatment with these agents did not result in hypoglycemia. In parallelstudies with an activator of both pancreatic and hepatic glucokinase,treatment was associated with insulin secretion and a reduction of bloodglucose below normal levels, i.e., hypoglycemia. Long term stimulationof insulin secretion is known to lead to pancreatic failure and anexacerbation of the diabetic condition as observed with the sulfonylureadrug class. Compounds of the current invention, by selectively targetingthe liver, also provide a safe mechanism of glucose lowering that avoidsinsulin secretion, hypoglycemia, and pancreatic burnout.

Thus, one aspect of the present invention provides for compounds ofgeneral Formula (I),

wherein:

X is selected from the group consisting of aryl, heteroaryl, alkyl,cycloalkyl, arylalkyl, aryloxy, heteroaryloxy, alkyloxy, cycloalkyloxyand arylalkyloxy;

R² is selected from the group consisting of aryl, heteroaryl, alkyl,cycloalkyl, arylalkyl, aryloxy, heteroaryloxy, alkyloxy, cycloalkyloxy,arylalkyloxy, arylthio, heteroarylthio, cycloalkylthio andarylalkylthio;

D is selected from heteroarylene and arylene, each optionallysubstituted;

G¹, G² and G³ are CR⁴ or N;

R⁴ is H, halogen or alkyl; and

R⁵⁰ is —R⁶¹-R⁶², and R⁶² is selected from —P(O)(Y²R⁵¹)R¹, or—P(O)(YR⁵¹)Y¹R⁵¹:

R⁶¹ is selected from null, arylene, heteroarylene, arylene-alkylene,alkylene-arylene, heteroarylene-alkylene, alkylene-heteroarylene,alkylene, alkenylene, alkynylene, alkylene-Q-alkylene, —CONR⁵²-alkylene,—COO-alkylene, —SO₂NR⁵²-alkylene, arylene-Q-alkylene,alkylene-Q-arylene, heteroarylene-Q-alkylene, alkylene-Q-heteroarylene,all optionally substituted;

Q is selected from O, S, SO, SO₂, NR⁵³;

With the proviso that when D is heteroarylene then R⁵⁰ is not—(CH₂)n′-Z′—(CH₂)m′-PO(OR₆₃)(OR₆₄), or —(CCH₂)n′-Z′—(CH₂)m′-PO(OR₆₃)R₆₅,or —(CH₂)n′-Z′—(CH₂)m′—O—PO(OR₆₃)R₆₅, or—(CH₂)n′-Z′—(CH₂)m′—O—PO(R₆₅)R₆₆, or —(CH₂)n′-Z′—(CH₂)m′-PO—(R₆₅)R₆₆;

R₆₃ and R₆₄ are the same or different and are independently selectedfrom the group consisting of hydrogen and alkyl, or R₆₃ and R₆₄ can becyclized into a ring;

R₆₅ and R₆₆ are the same or different and are independently selectedfrom the group consisting of alkyl, aryl, arylalkyl, heteroaryl, andheteroarylalkyl; or R₆₅ and R₆₆ can be cyclized into a ring, or R₆₃ andR₆₅ can be cyclized into a ring;

Z′ is selected from the group consisting of a bond, alkylene,alkenylene, 0, S, or SO₂;

m′ is 0, 1 or 2, provided that when Z is O, S or SO₂, n′ is 1 or 2;

n′ is 0, 1, or 2;

R¹ is selected from the group consisting of hydrogen, optionallysubstituted —C₁-C₆-alkyl, —CF₃, —CHF₂, —CH₂F, —CH₂OH, optionallysubstituted —C₂-C₆ alkenyl, optionally substituted —C₂-C₆ alkynyl,optionally substituted —(CR⁵² ₂)_(n)cycloalkyl, optionally substituted(CR⁵² ₂)_(n)heterocycloalkyl, —(CR⁵² ₂)_(k) S(═O)R⁵³, —(CR⁵²₂)_(k)S(O)₂R⁵³;

Y, Y¹ and Y² are each independently selected from —O— or —NR⁶⁰—;

wherein,

when Y² is —O— or when Y and Y¹ are both —O—, R⁵¹ attached to —O— isindependently selected from from the group consisting of —H, alkyl,optionally substituted aryl, optionally substituted heterocycloalkyl,optionally substituted —CH₂-heterocycloakyl with a cyclic moietycontaining a carbonate or thiocarbonate, optionally

substituted -alkylaryl, —C(R⁵²)₂OC(O)NR⁵² ₂, —NR⁵²—C(O)—R⁵³,—C(R⁵²)₂—OC(O)R⁵³, —C(R⁵²)₂—O—C(O)OR⁵³, —C(R⁵²)₂OC(O)SR⁵³,-alkyl-S—C(O)R⁵³, -alkyl-S—S-alkylhydroxy and -alkyl-S—S—S-alkylhydroxy,or

when Y² is —NR⁶⁰— or when Y and Y¹ are both —NR⁶⁰—, then R⁵¹ attached to—NR⁶⁰— is independently selected from the group consisting of —H,—[C(R⁵²)₂]_(r)—COOR⁵³, —C(R⁵⁴)₂COOR⁵³, —[C(R⁵²)₂]_(r)—C(O)SR⁵³, and-cycloalkylene-COOR⁵³; or

when Y is —O— and Y¹ is NR⁶⁰, then R⁵¹ attached to —O— is independentlyselected from —H, alkyl, optionally substituted aryl, optionallysubstituted heterocycloalkyl, optionally substituted CH₂-heterocycloakylwherein the cyclic moiety contains a carbonate or thiocarbonate,optionally substituted -alkylaryl, —C(R⁵²)₂OC(O)NR⁵² ₂, —NR⁵²—C(O)—R⁵³,—C(R⁵²)₂—OC(O)R⁵³, —C(R⁵²)₂—O—C(O)OR⁵³, —C(R⁵²)₂OC(O)SR⁵³,-alkyl-S—C(O)R⁵³, -alkyl-S—S-alkylhydroxy, and-alkyl-S—S—S-alkylhydroxy, and R⁵¹ attached to —NR⁶⁰— is independentlyselected from —H, —[C(R⁵²)₂]_(r)—COOR⁵³, —C(R⁵⁴)₂COOR⁵³,—[C(R⁵²)₂]_(r)—C(O)SR⁵³, and -cycloalkylene-COOR⁵³, wherein if both R⁵¹are alkyl, at least one is higher alkyl; or

when Y and Y¹ are independently selected from —O— and —NR⁶⁰—, then R⁵¹and R⁵¹ together form a cyclic group comprising -alkyl-S—S-alkyl-, orR⁵¹ and R⁵¹ together are the group

wherein,

V, W, and W′ are independently selected from the group consisting ofhydrogen, optionally substituted alkyl, optionally substituted aralkyl,heterocycloalkyl, aryl, substituted aryl, heteroaryl, substitutedheteroaryl, optionally substituted 1-alkenyl, and optionally substituted1-alkynyl, and

Z is —CHR⁵²OH, —CHR⁵²OC(O)R⁵³, —CHR⁵²OC(S)R⁵³, —CHR⁵²OC(S)OR⁵³,—CHR⁵²OC(O)SR⁵³, —CHR⁵²OCO₂R⁵³, —OR⁵², —SR⁵², —CHR⁵²N₃, —CH₂aryl,—CH(aryl)OH, —CH(CH═CR⁵² ₂)OH, —CH(C≡CR⁵²)OH, —R⁵², —NR⁵² ₂, —O COR⁵³,—OCO₂R⁵³, —SCOR⁵³, —SCO₂R⁵³, —NHCOR⁵², —NHCO₂R⁵³, —CH₂NHaryl,—(CH₂)_(r)—OR⁵² or —(CH₂)_(r)—SR⁵²; or

W and W′ are as defined above and together V and Z are connected via anadditional 3-5 atoms to form a cyclic group containing 5-7 atoms,wherein 0-1 atoms are heteroatoms and the remaining atoms are carbon; or

W′ and Z are as defined above and together V and W are connected via anadditional 3 carbon atoms to form an optionally substituted cyclic groupcontaining 6 carbon atoms or carbon substituted by hydrogen andsubstituted with one substituent selected from hydroxy, acyloxy,alkoxycarbonyloxy, alkylthiocarbonyloxy or aryloxycarbonyloxy which isattached to one of said carbon atoms that is three atoms from a Yattached to the phosphorus; or

V and W′ are as defined above and together Z and W are connected via anadditional 3-5 atoms to form a cyclic group, wherein 0-1 atoms areheteroatoms and the remaining atoms are carbon or carbon substituted byhydrogen, and V must be aryl, substituted aryl, heteroaryl, orsubstituted heteroaryl; or

V and Z are as defined above and together W and W′ are connected via anadditional 2-5 atoms to form a cyclic group, wherein 0-2 atoms areheteroatoms and the remaining atoms are carbon, where V must be aryl,substituted aryl, heteroaryl, or substituted heteroaryl;

R⁵² is R⁵³ or —H;

R⁵³ is alkyl, aryl, heterocycloalkyl or aralkyl;

R⁵⁴ is independently selected from —H or alkyl, or together R⁵⁴ and R⁵⁴form a cycloalkylene group;

R⁶⁰ is —H, lower alkyl, acyloxyalkyl, alkoxycarbonyloxyalkyl, loweracyl, C₁₋₆-perfluoroalkyl or NH(CR⁵⁵R⁵⁵)CH₃;

r is an integer 2 or 3;

f is an integer 0, 1 or 2;

wherein, V, Z, W, W′ are not all —H, and when Z is —R⁵², then at leastone of V, W, and W′ is not —H, alkyl, aralkyl, or heterocycloalkyl; and

pharmaceutically acceptable salts, co-crystals and prodrugs thereof.

One embodiment includes compounds of formula I wherein:

X is selected from the group consisting of alkyloxy, cycloalkyloxy,alkyl and cycloalkyl;

R² is -E¹-E²-E³, wherein,

E¹ is a bond, O or S;

E² is a bond or alkylene;

wherein, when both E¹ and E² are a bond, together they form a singlebond;

E³ is optionally substituted —C₁₋₄-alkyl, optionally substituted—C₃₋₈-cycloalkyl or aryl, optionally substituted with one or two groupsindependently selected from the group consisting of aryl, heteroaryl,halogen, —C₁₋₄-alkyl, —S(O)₂R⁵ or —OR⁵ or R² selected from the groupconsisting of —C₁₋₄-alkyloxy, —C₃₋₆-cycloalkyloxy, benzyloxy,2-(2-thienyl)ethyloxy, 2-(3-thienyl)ethyloxy, and phenyloxy, eachoptionally substituted with one or two groups independently selectedfrom the group consisting of halogen, —C₁₋₄-alkyl, —S(O)₂C₁₋₄-alkyl,—S(O)₂C₃₋₆-cycloalkyl, or —OC₁₋₄-alkyl;

R⁵ is alkyl or cycloalkyl;

D is heteroarylene, said heteroarylene comprising a nitrogen ring atomadjacent to a carbon ring atom, wherein said carbon ring atom isconnected to the amide nitrogen atom adjacent to D, and wherein saidheteroarylene has an additional 0 to 3 heteroatoms independentlyselected from O, S or N;

G¹ is CH;

G² is CH or N;

G³ is CH; and

R⁵⁰ is —R⁶¹-R⁶², and R⁶² is selected from —P(O)(Y²R⁵¹)R¹, or—P(O)(YR⁵¹)Y¹R⁵¹.

One embodiment includes compounds of formula I wherein D is aheteroarylene substituted with one or two groups independently selectedfrom halogen and optionally substituted C₁₋₄-alkyl.

One embodiment includes compounds of formula I wherein, D isheteroarylene having a nitrogen as a ring atom, said nitrogen ring atomconnected to a ring carbon atom, wherein said ring carbon atom isconnected to the amide nitrogen atom that is adjacent to D, and whereinsaid heteroarylene has an additional 0 to 3 heteroatoms independentlyselected from O, S or N;

One embodiment includes compounds of formula I wherein:

X is isopropyloxy or benzyloxy;

R² is selected from the group consisting of n-propyloxy, isopropyloxy,2-methylpropyloxy, cylclopentylmethyloxy, benzyloxy,2-(2-thienyl)ethyloxy, 2-(3-thienyl)ethyloxy, 2-fluorophenylmethyloxy,4-methylsulfonylphenyloxy, 4-ethylsulfonylphenyloxy and4-isopropylsulfonylphenyloxy;

D is pyridine-diyl or

G¹ is CH;

G² is CH;

G³ is CH; and

R⁵⁰ is —R⁶¹-R⁶², and R⁶² is selected from —P(O)(Y²R⁵¹)R¹, or—P(O)(YR⁵¹)Y¹R⁵¹.

One embodiment includes compounds of formula I wherein, D is aheteroarylene selected from the group consisting of pyridine-diyl,thiazole-diyl, thiadiazole-diyl, pyrazol-diyl, pyrazine-diyl,pyridazine-diyl and pyrimidine-diyl, each optionally substituted withone or two groups independently selected from halogen and optionallysubstituted C₁₋₄-alkyl; wherein, when said heteroarylene ispyridino-diyl, pyrazole-diyl, pyridaze-diyl or pyrimidine-diyl, the ringatom at position 5 of said heteroarylene is connected to R⁵⁰ and whensaid heteroarylene is thiazole-diyl or thiadiazole-diyl, the ring atomat position 4 of said heteroarylene is connected to R⁵⁰.

Another aspect of the present invention provides for compounds ofgeneral Formula II

wherein:

X is selected from the group consisting of aryl, heteroaryl, alkyl,cycloalkyl, arylalkyl, aryloxy, heteroaryloxy, alkyloxy, cycloalkyloxyand arylalkyloxy, and

G² is CR⁴ or N, or

together G² and X are connected to form a cyclic group containing 5-7atoms, wherein 0-2 ring atoms of said cyclic group are heteroatoms andthe remaining ring atoms of said cyclic group are carbon atomsoptionally substituted with alkyl, aryl, cycloalkyl or heteroaryl;

R² is selected from the group consisting of arylene, heteroarylene,alkylene, cycloalkylene, arylalkylene, alkylarylene, arylene-O—,heteroarylene-O—, alkylene-O—, cycloalkylene-O—, arylalkylene-O—,alkylarylene-O—, arylene-S—, arylene-SO₂, -heteroarylene-S—,heteroarylene-SO₂—, alkylene-S—, alkylene-SO₂—, cycloalkylene-S—,cycloalkylene-SO₂—; arylalkylene-S—, arylalkylene-SO₂—, alkylarylene-S—;

G¹ is CR⁴ or N;

G³ is CR⁴ or N;

R⁴ is H, halogen or optionally substituted alkyl;

D is selected from a group consisting of heteroaryl and aryl;

R⁵⁰ is —P(O)(Y²R⁵¹) R¹ or —P(O)(YR⁵¹)Y¹R⁵¹;

R¹ is selected from the group consisting of hydrogen, optionallysubstituted —C₁-C₆-alkyl, —CF₃, —CHF₂, —CH₂F, —CH₂OH, optionallysubstituted —C₂-C₆ alkenyl, optionally substituted —C₂-C₆ alkynyl,optionally substituted —(CR⁵² ₂)_(n)cycloalkyl, optionally substituted(CR⁵² ₂)_(n)heterocycloalkyl, —(CR⁵² ₂)_(k) S(═O)R⁵³, —(CR⁵²₂)_(k)S(═O)₂R⁵³;

Y, Y¹ and Y² are each independently selected from —O— or —NR⁶⁰—;

wherein,

when Y² is —O— or when Y and Y¹ are both —O—, R⁵¹ attached to —O— isindependently selected from —H, optionally substituted aryl, optionallysubstituted heterocycloalkyl, optionally substituted—CH₂-heterocycloakyl wherein the cyclic moiety contains a carbonate orthiocarbonate, optionally substituted -alkylaryl, —C(R⁵²)₂OC(O)NR⁵² ₂,—NR⁵²—C(O)—R⁵³, —C(R⁵²)₂—OC(O)R⁵³, —C(R⁵²)₂—O—C(O)OR⁵³,—C(R⁵²)₂OC(O)SR⁵³, -alkyl-S—C(O)R⁵³, -alkyl-S—S-alkylhydroxy, and-alkyl-S—S—S-alkylhydroxy; or

when Y² is —NR⁶⁰— or when Y and Y¹ are both —NR⁶⁰—, then R⁵¹ attached to—NR⁶⁰— is independently selected

from —H, —[C(R⁵²)₂]_(r)—COOR⁵³, —C(R⁵⁴)₂COOR⁵³, —[C(R⁵²)₂]_(r)—C(O)SR⁵³,and -cycloalkylene-COOR⁵³; or

when Y is —O— and Y¹ is NR⁶⁰, then R⁵¹ attached to —O— is independentlyselected from —H, alkyl, optionally substituted aryl, optionallysubstituted heterocycloalkyl, optionally substituted CH₂-heterocycloakylwherein the cyclic moiety contains a carbonate or thiocarbonate,optionally

substituted -alkylaryl, —C(R⁵²)₂OC(O)NR⁵² ₂, —NR⁵²—C(O)—R⁵³,—C(R⁵²)₂—OC(O)R⁵³, —C(R⁵²)₂—O—C(O)OR⁵³, —C(R⁵²)₂OC(O)SR⁵³,-alkyl-S—C(O)R⁵³, -alkyl-S—S-alkylhydroxy,and -alkyl-S—S—S-alkylhydroxy, and R⁵¹ attached to —NR⁶⁰— isindependently selected from —H, —[C(R⁵²)₂]_(r)—COOR⁵³,—C(R⁵⁴)₂COOR⁵³, —[C(R⁵²)₂]_(r)—C(O)SR⁵³, and -cycloalkylene-COOR⁵³,wherein if both R⁵¹ are alkyl, at least one is higher alkyl; or

when Y and Y¹ are independently selected from —O— and —NR⁶⁰—, then R⁵¹and R⁵¹ together form a cyclic group comprising -alkyl-S—S-alkyl-, orR⁵¹ and R⁵¹ together are the group

wherein,

V, W, and W′ are independently selected from the group consisting ofhydrogen, optionally substituted alkyl, optionally substituted aralkyl,heterocycloalkyl, aryl, substituted aryl, heteroaryl, substitutedheteroaryl, optionally substituted 1-alkenyl, and optionally substituted1-alkynyl, and

Z is —CHR⁵²OH, —CHR⁵²OC(O)R⁵³, —CHR⁵²OC(S)R⁵³, —CHR⁵²OC(S)OR⁵³,—CHR⁵²OC(O)SR⁵³, —CHR⁵²OCO₂R⁵³, —OR⁵², —SR⁵², —CHR⁵²N₃, —CH₂aryl,—CH(aryl)OH, —CH(CH═CR⁵² ₂)OH, —CH(C≡CR⁵²)OH, —R⁵², —NR⁵² ₂, —OCOR⁵³,—OCO₂R⁵³, —SCOR⁵³, —SCO₂R⁵³, —NHCOR⁴², —NHCO₂R⁵³, —CH₂NHaryl,—(CH₂)_(r)—OR⁵² or —(CH₂)_(r)—SR⁵²; or

W and W are as defined above and together V and Z are connected via anadditional 3-5 atoms to form a cyclic group containing 5-7 atoms,wherein 0-1 atoms are heteroatoms and the remaining atoms are carbon; or

W′ and Z are as defined above and together V and W are connected via anadditional 3 carbon atoms to form an optionally substituted cyclic groupcontaining 6 carbon atoms or carbon substituted by hydrogen andsubstituted with one substituent selected from hydroxy, acyloxy,alkoxycarbonyloxy, alkylthiocarbonyloxy or aryloxycarbonyloxy which isattached to one of said carbon atoms that is three atoms from a Yattached to the phosphorus; or

V and W′ are as defined above and together Z and W are connected via anadditional 3-5 atoms to form a cyclic group, wherein 0-1 atoms areheteroatoms and the remaining atoms are carbon or carbon substituted byhydrogen, and V must be aryl, substituted aryl, heteroaryl, orsubstituted heteroaryl; or

V and Z are as defined above and together W and W′ are connected via anadditional 2-5 atoms to form a cyclic group, wherein 0-2 atoms areheteroatoms and the remaining atoms are carbon, where V must be aryl,substituted aryl, heteroaryl, or substituted heteroaryl;

R⁵² is R⁵³ or —H;

R⁵³ is alkyl, aryl, heterocycloalkyl or aralkyl;

R⁵⁴ is independently selected from —H or alkyl, or together R⁵⁴ and R⁵⁴form a cycloalkylene group;

R⁶⁰ is —H, lower alkyl, acyloxyalkyl, alkoxycarbonyloxyalkyl, loweracyl, C₁₋₆-perfluoroalkyl or NH(CR⁵⁵R⁵⁵)_(f)CH₃;

r is an integer 2 or 3;

f is an integer 0, 1 or 2;

wherein, V, Z, W, W′ are not all —H, and when Z is —R⁵², then at leastone of V, W, and W′ is not —H, alkyl, aralkyl, or heterocycloalkyl; and

pharmaceutically acceptable salts and prodrugs thereof.

One embodiment includes compounds of formula II wherein:

X is selected from the group consisting of aryl, heteroaryl, alkyl,cycloalkyl, arylalkyl, aryloxy, alkyloxy, cycloalkyloxy andarylalkyloxy;

R² is -E¹-E²-E³-E⁴-, wherein E⁴ is connected to R⁵⁰;

E¹ is a bond, O or S;

E² is a bond or alkylene;

E³ is optionally substituted C₁₋₄-alkylene, optionally substitutedC₃₋₈-cycloalkylalkylene, arylene or heteroarylene optionally substitutedwith one or two groups independently selected from aryl, heteroaryl,cycloalkyl, cycloalkenyl, halogen, CN, CF₃, NR⁵ ₂, —C₁₋₄-alkyl, —S(O)₂R⁵or —OR⁵; wherein, when both E¹ and E² are a bond, together they form asingle bond;

R⁵ is optionally substituted alkyl or cycloalkyl;

E⁴ is a bond or alkylene;

G¹ is CH;

G² is CH;

G³ is CH;

D is heteroaryl having a nitrogen as a ring atom, said heteroarylcomprising a nitrogen ring atom adjacent to a carbon ring atom, whereinsaid carbon ring atom is connected to the amide nitrogen atom adjacentto D, and wherein said heteroaryl has an additional 0 to 3 heteroatomsindependently selected from O, S or N; and

R⁵⁰ is —P(O)(Y²R⁵¹) R¹ or —P(O)(YR⁵¹)Y¹R⁵¹.

One embodiment includes compounds of formula II wherein:

X is selected from the group consisting of isopropyloxy, benzyloxy,1,3-difluoroprop-2-yloxy, cyclopentyloxy, phenyloxy,3,5-dimethylisoxazol-2-yl, phenyl and 2-methylpropyl;

R² is selected from the group consisting of phenylene-O—,methylene-phenylene-O—, phenylene-methylene-O—, furan-2-yl-5-methylene,thiophen-2-yl-5-methylene, pyridin-diyl-O—, pyrimidin-diyl-O—,pyridazin-diyl-O— and pyrazin-diyl-O—, each optionally substituted withone or two groups independently selected from aryl, heteroaryl, halogen,CN, CF₃, NR⁵ ₂, —C₁₋₄-alkyl, —S(O)₂R⁵ or —OR⁵, wherein R⁵⁰ is connectedto R² by a carbon atom.

G¹ is CH;

G² is CH;

G³ is CH;

D is selected from the group consisting of pyridinyl, thiazolyl,1,3,4-thiadiazolyl, 1,2,4-thiadiazolyl, oxazolyl, isoxazolyl, pyrazolyl,pyrazinyl, pyridazinyl, pyrimidinyl, benzothiazolyl and5,6-dihydro-4H-cyclopentathiazolyl, each optionally substituted with oneor two groups selected from halogen, CF₃, optionally substituted orC₁₋₄-alkyl; and,

R⁵⁰ is —P(O)(YR⁵¹)Y¹R⁵¹.

In one embodiment, compounds of the invention (formulas I and II) underthe conditions of Human Enzyme Assay of Example A, at a concentration of100 μM are able to activate 50 μg of human glucokinase by at least 150%.In other embodiments, compounds of the invention are able to activateglucokinsae by at least 160%, 170%, 180%, 190%, 200%, 210%, 220%, 230%,240%, 250%, 260%, 270%, 280%, 290%, 300%, 310%, 320%, 330%, 340%, 350%,360%, 370%, 380%, 390%, 400%, 410%, 420%, 430%, 440%, 450%, 460%, 470%,480%, 490%, 500% or at least 600% as compared to glucokinase in theabsence of said compound of the present invention.

In one embodiment, compounds of the invention have an EC₅₀ of less thanor equal to 5 μM in rat hepatocyte (conditions of Example B).

In one embodiment, compounds of the invention have an EC₅₀ of less thanor equal to 1 μM in rat hepatocyte (conditions of Example B).

In one embodiment, compounds of the invention have an EC₅₀ of less thanor equal to 500 nM in rat hepatocyte (conditions of Example B).

One embodiment includes compounds of the invention wherein R⁵⁰ isselected from the group consisting of —PO₃H₂, —P(O)[—OCR⁵² ₂OC(O)R⁵³]₂,—P(O)[—OCR⁵² ₂OC(O)OR⁵³]₂, —P(O)[—N(H)CR⁵² ₂C(O)OR⁵³]₂,—P(O)[—O-alk-SC(O)R⁵³]₂, —P(O)[—OCR⁵² ₂OC(O)R⁵³][—R¹], —P(O)[—OCR⁵²₂OC(O)OR⁵³][—R¹], —P(O)[—N(H)CR⁵² ₂C(O)OR⁵³][—R¹],—P(O)[—OCH₂CH₂SC(O)R⁵³][—R¹], —P(O)(OH)(YR⁵¹), —P(O)(OR⁵⁶)(OR⁵⁶),—P(O)(OH)(—R¹), —P(O)[—OCR⁵² ₂OC(O)R⁵³](OR⁵⁶), —P(O)[—OCR⁵²₂OC(O)OR⁵³](OR⁵⁶), —P(O)[—N(H)CR⁵² ₂ C(O)OR⁵³](OR⁵⁶), P(O)(OH)(NH₂), and—P(O)[—OCH(V)CH₂CH₂O—];

V is optionally substituted aryl or optionally substituted heteroaryl;

R⁵⁶ is —C₁-C₁₂ alkyl, —C₂-C₁₂ alkenyl, —C₂-C₁₂ alkynyl, —(CR⁵⁷₂)_(n)aryl, —(CR⁵⁷ ₂)_(n)cycloalkyl, or —(CR⁵⁷ ₂)_(n)heterocycloalkyl,each optionally substituted;

each R⁵⁷ is independently selected from the group consisting ofhydrogen, optionally substituted —C₁-C₄ alkyl, halogen, optionallysubstituted —O—C₁-C₄ alkyl, —OCF₃, optionally substituted —S—C₁-C₄alkyl, —NR⁵⁸R⁵⁹, optionally substituted —C₂-C₄ alkenyl, and optionallysubstituted —C₂-C₄ alkynyl; with the proviso that when one R⁵⁷ isattached to C through an O, S, or N atom, then the other R⁵⁷ attached tothe same C is a hydrogen, or attached via a carbon atom;

R⁵⁸ is selected from hydrogen and optionally substituted —C₁-C₄ alkyl;and,

R⁵⁹ is selected from the group consisting of hydrogen and optionallysubstituted —C₁-C₄ alkyl, optionally substituted —C(O)—C₁-C₄ alkyl and—C(O)H.

One embodiment includes compounds of the invention wherein R⁵⁰ isselected from the group consisting of, —P(O)(OH)₂,—P(O)[—OCH₂OC(O)-t-butyl]₂, —P(O)[—OCH(CH₃)OC(O)-t-butyl]₂,—P(O)[—OCH(CH₃)OC(O)O-i-propyl]₂, —P(O)[—OCH₂OC(O)O-i-propyl]₂,—P(O)[—N(H)CH(CH₃)C(O)OCH₂CH₃]₂, —P(O)[—N(H)C(CH₃)C(O)OCH₂CH₃]₂,—P(O)[—N(H)CH(CH₃)C(O)OCH₂CH₃][3,4-methylene dioxyphenyl],—P(O)[—N(H)C(CH₃)₂C(O)OCH₂CH₃][3,4-methylenedioxyphenyl],—P(O)[—O—CH₂CH₂S—C(O)CH₃]₂, —P(O)(OH)(OCH₃), —P(O)(OH)(OCH₂CH₃),—P(O)(OH)(CH₃), —P(O)[—OCH(3-chlorophenyl)CH₂CH₂O—],—P(O)[—OCH(pyrid-4-yl)CH₂CH₂O—], —P(O)[—OCH₂OC(O)-t-butyl](OCH₃),—P(O)[—OCH₂OC(O)O-i-propyl](OCH₃), —P(O)[—OCH(CH₃)OC(O)-t-butyl](OCH₃),—P(O)[—OCH(CH₃)OC(O)O-i-propyl](OCH₃),—P(O)[—N(H)CH(CH₃)C(O)OCH₂CH₃](OCH₃),—P(O)[—N(H)CH(CH₃)C(O)OCH₂CH₃](CH₃),—P(O)[—N(H)C(CH₃)₂C(O)OCH₂CH₃](OCH₃),—P(O)[—N(H)C(CH₃)₂C(O)OCH₂CH₃](CH₃), —P (O)[—OCH₂OC(O)-t-butyl](CH₃),—P(O)[—OCH₂OC(O)O-i-propyl](CH₃), —P(O)[—OCH(CH₃)OC(O)-t-butyl](CH₃),—P(O)[—OCH(CH₃)OC(O)O-i-propyl](CH), and —P(O)[—OCH₂OC(O)O-ethyl]₂.

In another embodiment, Y and Y¹ are each independently selected from —O—and —NR⁶⁰—; and together R⁵¹ and R⁵¹ are the group

wherein, V is substituted aryl or substituted heteroaryl.

In a further embodiment, Z is —H, W is —H, and W′ is —H.

In a further embodiment, V is 3-chlorophenyl, 4-chlorophenyl,3-bromophenyl, 3-fluorophenyl, pyrid-4-yl, pyrid-3-yl or3,5-dichlorophenyl.

In a further embodiment, the relative stereochemistry between theV-group substituent and the carbon attached to the P atom of R⁵⁰ is cis.

In a further embodiment, the relative stereochemistry between theV-group substituent and the carbon attached to the P atom of R⁵⁰ istrans.

In a further embodiment, said compound has R stereochemistry at thecarbon where the V-group is attached.

In a further embodiment, the compound has S stereochemistry at thecarbon where the V-group is attached.

In one aspect of the invention, the following non-limiting embodimentsare provided. For example, one embodiment (“Embodiment 1”) is a compoundof general Formula (I),

wherein:

X is selected from the group consisting of aryl, heteroaryl, alkyl,cycloalkyl, arylalkyl, aryloxy, heteroaryloxy, alkyloxy, cycloalkyloxyand arylalkyloxy;

R² is selected from the group consisting of aryl, heteroaryl, alkyl,cycloalkyl, arylalkyl, aryloxy, heteroaryloxy, alkyloxy, cycloalkyloxy,arylalkyloxy, arylthio, heteroarylthio, cycloalkylthio andarylalkylthio;

D is selected from heteroarylene and arylene, each optionallysubstituted;

G¹, G² and G³ are CR⁴ or N;

R⁴ is H, halogen or alkyl; and

R⁵⁰ is —R⁶¹-R⁶², and R⁶² is selected from —P(O)(Y²R⁵¹)R¹, or—P(O)(YR⁵¹)Y¹R⁵¹;

R⁶¹ is selected from null, arylene, heteroarylene, arylene-alkylene,alkylene-arylene, heteroarylene-alkylene, alkylene-heteroarylene,alkylene, alkenylene, alkynylene, alkylene-Q-alkylene, —CONR⁵²-alkylene,—COO-alkylene, —SO₂NR⁵²-alkylene, arylene-Q-alkylene,alkylene-Q-arylene, heteroarylene-Q-alkylene, alkylene-Q-heteroarylene,all optionally substituted;

Q is selected from O, S, SO, SO₂, NR⁵³;

with the proviso that when D is heteroarylene then R⁵⁰ is not—(CH₂)n′-Z′—(CH₂)m′-PO(OR⁶³)(OR⁶⁴), or —(CCH₂)n′-Z′—(CH₂)m′-PO(OR⁶³)R⁶⁵,or —(CH₂)n′-Z′—(CH₂)m′—O—PO(OR⁶³)R⁶⁵, or—(CH₂)n′-Z′—(CH₂)m′—O—PO(R⁶⁵)R⁶⁶, or —(CH₂)n′-Z′—(CH₂)m′-PO—(R⁶⁵)R⁶⁶;

R⁶³ and R⁶⁴ are the same or different and are independently selectedfrom the group consisting of hydrogen and alkyl, or R⁶³ and R⁶⁴ can becyclized into a ring;

R⁶⁵ and R⁶⁶ are the same or different and are independently selectedfrom the group consisting of alkyl, aryl, arylalkyl, heteroaryl, andheteroarylalkyl; or R⁶⁵ and R⁶⁶ can be cyclized into a ring, or R⁶³ andR⁶⁵ can be cyclized into a ring;

Z′ is selected from the group consisting of a bond, alkylene,alkenylene, O, S, or SO₂;

m′ is 0, 1 or 2, provided that when Z is 0, S or SO₂, n′ is 1 or 2;

n′ is 0, 1, or 2;

R¹ is selected from the group consisting of hydrogen, optionallysubstituted —C₁-C₆-alkyl, —CF₃, —CHF₂, —CH₂F, —CH₂OH, optionallysubstituted —C₂-C₆ alkenyl, optionally substituted —C₂-C₆ alkynyl,optionally substituted —(CR⁵² ₂)_(n)cycloalkyl, optionally substituted(CR⁵² ₂)_(n)heterocycloalkyl, —(CR⁵² ₂)_(k) S(═O)R⁵³, —(CR⁵²₂)_(k)S(═O)₂R⁵³;

Y, Y¹ and Y² are each independently selected from —O— or —NR¹—;

wherein,

when Y² is —O— or when Y and Y¹ are both —O—, R⁵¹ attached to —O— isindependently selected from from the group consisting of —H, alkyl,optionally substituted aryl, optionally substituted heterocycloalkyl,optionally substituted

—CH₂-heterocycloakyl with a cyclic moiety containing a carbonate orthiocarbonate, optionallysubstituted -alkylaryl, —C(R⁵²)₂OC(O)NR⁵² ₂, —NR⁵²—C(O)—R⁵³,—C(R⁵²)₂—OC(O)R⁵³, —C(R⁵²)₂—O—C(O)OR⁵³, —C(R⁵²)₂OC(O)SR⁵³,-alkyl-S—C(O)R⁵³, -alkyl-S—S-alkylhydroxyand -alkyl-S—S—S-alkylhydroxy; or

when Y² is —NR⁶⁰— or when Y and Y¹ are both —NR⁶⁰—, then R⁵¹ attached to—NR⁵⁰— is independently selected from the group consisting

of —H, —[C(R⁵²)₂]_(r)—COOR⁵³, —C(R⁵⁴)₂COOR⁵³, —[C(R⁵²)₂]_(r)—C(O)SR⁵³,and -cycloalkylene-COOR⁵³; or

when Y is —O— and Y¹ is NR⁶⁰, then R⁵¹ attached to —O— is independentlyselected from —H, alkyl, optionally substituted aryl, optionallysubstituted heterocycloalkyl, optionally substituted CH₂-heterocycloakylwherein the cyclic moiety contains a carbonate or thiocarbonate,optionally

substituted -alkylaryl, —C(R⁵²)₂OC(O)NR⁵² ₂, —NR⁵²—C(O)—R⁵³,—C(R⁵²)₂—OC(O)R⁵³, —C(R⁵²)₂—O—C(O)OR⁵³, —C(R⁵²)₂OC(O)SR⁵³,-alkyl-S—C(O)R⁵³, -alkyl-S—S-alkylhydroxy, and-alkyl-S—S—S-alkylhydroxy, and R⁵¹ attached to —NR⁶⁰— is independentlyselected from —H, —[C(R⁵²)₂]_(r)—COOR⁵³, —C(R⁵⁴)₂COOR⁵³,—[C(R⁵²)₂]_(r)—C(O)SR⁵³, and -cycloalkylene-COOR⁵³, wherein if both R⁵¹are alkyl, at least one is higher alkyl; or

when Y and Y¹ are independently selected from —O— and —NR⁶⁰—, then R⁵¹and R⁵¹ together form a cyclic group comprising -alkyl-S—S-alkyl-, orR⁵¹ and R⁵¹ together are the group

wherein,

V, W, and W′ are independently selected from the group consisting ofhydrogen, optionally substituted alkyl, optionally substituted aralkyl,heterocycloalkyl, aryl, substituted aryl, heteroaryl, substitutedheteroaryl, optionally substituted 1-alkenyl, and optionally substituted1-alkynyl, and

Z is —CHR⁵²OH, —CHR⁵²OC(O)R⁵³, —CHR⁵²OC(S)R⁵³, —CHR⁵²OC(S)OR⁵³,—CHR⁵²OC(O)SR⁵³, —CHR⁵²OCO₂R⁵³, —OR⁵², —SR⁵², —CHR⁵²N₃, —CH₂aryl,—CH(aryl)OH, —CH(CH═CR⁵² ₂)OH, —CH(C≡CR⁵²)OH, —R⁵², —NR⁵² ₂, —O COR⁵³,—OCO₂R⁵³, —SCOR⁵³, —SCO₂R⁵³, —NHCOR⁵², —NHCO₂R⁵³, —CH₂NHaryl,—(CH₂)_(r)—OR⁵² or —(CH₂)_(r)—SR⁵²; or

W and W′ are as defined above and together V and Z are connected via anadditional 3-5 atoms to form a cyclic group containing 5-7 atoms,wherein 0-1 atoms are heteroatoms and the remaining atoms are carbon; or

W′ and Z are as defined above and together V and W are connected via anadditional 3 carbon atoms to form an optionally substituted cyclic groupcontaining 6 carbon atoms or carbon substituted by hydrogen andsubstituted with one substituent selected from hydroxy, acyloxy,alkoxycarbonyloxy, alkylthiocarbonyloxy or aryloxycarbonyloxy which isattached to one of said carbon atoms that is three atoms from a Yattached to the phosphorus; or

V and W′ are as defined above and together Z and W are connected via anadditional 3-5 atoms to form a cyclic group, wherein 0-1 atoms areheteroatoms and the remaining atoms are carbon or carbon substituted byhydrogen, and V must be aryl, substituted aryl, heteroaryl, orsubstituted heteroaryl; or

V and Z are as defined above and together W and W′ are connected via anadditional 2-5 atoms to form a cyclic group, wherein 0-2 atoms areheteroatoms and the remaining atoms are carbon, where V must be aryl,substituted aryl, heteroaryl, or substituted heteroaryl;

R⁵² is R⁵³ or —H;

R⁵³ is alkyl, aryl, heterocycloalkyl or aralkyl;

R⁵⁴ is independently selected from —H or alkyl, or together R⁵⁴ and R⁵⁴form a cycloalkylene group;

R⁶⁰ is —H, lower alkyl, acyloxyalkyl, alkoxycarbonyloxyalkyl, loweracyl, C₁₋₆-perfluoroalkyl or NH(CR⁵⁵R⁵⁵)_(f)CH₃;

r is an integer 2 or 3;

f is an integer 0, 1 or 2;

wherein, V, Z, W, W′ are not all —H, and when Z is —R⁵², then at leastone of V, W, and W′ is not —H, alkyl, aralkyl, or heterocycloalkyl; and

pharmaceutically acceptable salts, co-crystals and prodrugs thereof.

A further embodiment (“Embodiment 2”) is the compound of embodiment 1,wherein X is selected from the group consisting of alkyl, cycloalkyl,alkyloxy, cycloalkyloxy and aryloxy.

A further embodiment (“Embodiment 3”) is the compound of embodiment 1,wherein X is selected from the group consisting of alkyloxy andcycloalkyloxy.

A further embodiment (“Embodiment 4”) is the compound of embodiment 1,wherein R² is -E¹-E²-E³, wherein,

E¹ is a bond, O or S;

E² is a bond or alkylene;

wherein, when both E¹ and E² are a bond, together they form a singlebond;

E¹ is optionally substituted —C₁₋₄-alkyl, optionally substituted—C₃₋₈-cycloalkyl or aryl optionally substituted with one or two groupsindependently selected from the group consisting of aryl, heteroaryl,halogen, —C₁₋₄-alkyl, —S(O)₂R⁵ or —OR⁵;

R⁵ is alkyl or cycloalkyl.

A further embodiment (“Embodiment 5”) is the compound of embodiment 1,wherein R² is selected from the group consisting of —C₁₋₄-alkyloxy,—C₃₋₆-cycloalkyloxy, benzyloxy, 2-(2-thienyl)ethyloxy,2-(3-thienyl)ethyloxy, and phenyloxy, each optionally substituted withone or two groups independently selected from the group consisting ofhalogen, —C₁₋₄-alkyl, —S(O)₂C₁₋₄-alkyl, —S(O)₂C₃₋₆-cycloalkyl, or—OC₁₋₄-alkyl.

A further embodiment (“Embodiment 6”) is the compound of embodiment 1,wherein R² is selected from the group consisting of n-propyloxy,isopropyloxy, 2-methylpropyloxy, cylclopentylmethyloxy, benzyloxy,2-(2-thienyl)ethyloxy, 2-(3-thienyl)ethyloxy, 2-fluorophenylmethyloxy,4-methylsulfonylphenyloxy, 4-ethylsulfonylphenyloxy and4-isopropylsulfonylphenyloxy.

A further embodiment (“Embodiment 7”) is the compound of embodiment 1,wherein D is heteroarylene, said heteroarylene comprising a nitrogenring atom adjacent to a carbon ring atom, wherein said carbon ring atomis connected to the amide nitrogen atom adjacent to D, and wherein saidheteroarylene has an additional 0 to 3 heteroatoms independentlyselected from O, S or N.

A further embodiment (“Embodiment 8”) is the compound of embodiment 1,wherein D is a heteroarylene, optionally substituted with one or twogroups independently selected from halogen and optionally substitutedC₁₋₄-alkyl; wherein, when said heteroarylene is pyridine-diyl,pyrazole-diyl, pyridaze-diyl or pyramidine-diyl, the ring atom atposition 5 of said heteroarylene is connected to R⁵⁰ and when saidheteroarylene is thiazole-diyl or thiadiazole-diyl, the ring atom atposition 4 of said heteroarylene is connected to R⁵⁰, and n is 0 or 1.

A further embodiment (“Embodiment 9”) is the compound of embodiment 1,wherein G¹, G² and G³ are CR⁴ and R⁴ is H, halogen or alkyl.

A further embodiment (“Embodiment 10”) is the compound of embodiment 9,wherein R⁴ is H.

A further embodiment (“Embodiment 11”) is the compound of embodiment 1,wherein R⁶² is selected from the group consisting

of —PO₃H₂, —P(O)[—OCR⁵² ₂OC(O)R⁵³]₂, —P(O)[—OCR⁵² ₂OC(O)OR⁵³]₂,—P(O)[—N(H)CR⁵² ₂C(O) OR⁵³]₂, —P(O)[—O-alk-SC(O)R⁵³]₂, —P(O)[—OCR⁵²₂OC(O)R⁵³][—R¹], —P(O)[—OCR⁵² ₂OC(O)OR⁵³][—R¹],—P(O)[—N(H)CR⁵²C(O)OR⁵³][—R¹], —P(O)[—OCH₂CH₂SC(O)R⁵³][—R¹],—P(O)(OH)(YR⁵¹), —P(O)(OR⁵⁶)(OR⁵⁶), —P(O)(OH)(—R¹), —P(O)[—OCR⁵²₂OC(O)R⁵³](OR⁵⁶), —P(O)[—OCR⁵² ₂OC(O)OR⁵³](OR⁵⁶), P(O)[—N(H)CR⁵²₂C(O)OR⁵³](OR⁵⁶), P(O)(OH)(NH₂), and —P(O)[—OCH(V)CH₂CH₂O—];

V is optionally substituted aryl or optionally substituted heteroaryl;

R⁵⁶ is —C₁-C₁₂ alkyl, —C₂-C₁₂ alkenyl, —C₂-C₁₂ alkynyl, —(CR⁵⁷₂)_(n)aryl, —(CR⁵⁷ ₂)_(n)cycloalkyl, or —(CR⁵⁷ ₂)_(n)heterocycloalkyl,each optionally substituted;

each R⁵⁷ is independently selected from the group consisting ofhydrogen, optionally substituted —C₁-C₄ alkyl, halogen, optionallysubstituted —O—C₁-C₄ alkyl, —OCF₃, optionally substituted —S—C₁-C₄alkyl, —NR⁵⁸R⁵⁹, optionally substituted —C₂-C₄ alkenyl, and optionallysubstituted —C₂-C₄ alkynyl; with the proviso that when one R⁵⁷ isattached to C through an O, S, or N atom, then the other R⁵⁷ attached tothe same C is a hydrogen, or attached via a carbon atom;

R⁵⁸ is selected from hydrogen and optionally substituted —C₁-C₄ alkyl;and,

R⁵⁹ is selected from the group consisting of hydrogen and optionally

substituted —C₁-C₄ alkyl, optionally substituted —C(O)—C₁-C₄ alkyl and—C(O)H.

A further embodiment (“Embodiment 12”) is the compound of embodiment 1,wherein R⁶² is selected from the group consisting of:

P(O)(OH)₂, —P(O)[—OCH₂OC(O)-t-butyl]₂, —P(O)[—OCH(CH₃)OC(O)-t-butyl]₂,—P(O)[—OCH(CH₃)OC(O)O-i-propyl]₂, —P(O)[—OCH₂OC(O)O-i-propyl]₂,—P(O)[—N(H)CH(CH₃)C(O)OCH₂CH₃]₂, —P(O)[—N(H)C(CH₃)₂C(O)OCH₂CH₃]₂,—P(O)[—N(H) CH(CH₃)C(O)OCH₂CH₃][3,4-methylenedioxyphenyl],—P(O)[—N(H)C(CH₃)₂C(O)OCH₂CH₃][3,4-methylenedioxyphenyl],—P(O)[—O—CH₂CH₂S—C(O)CH₃]₂, —P(O)(OH)(OCH₃), —P(O)(OH)(OCH₂CH₃),—P(O)(OH)(CH₃), —P(O)[—OCH(3-chlorophenyl)CH₂CH₂O—],—P(O)[—OCH(pyrid-4-yl)CH₂CH₂O—], —P(O)[—OCH₂OC(O)-t-butyl](OCH₃),—P(O)[—OCH₂OC(O)O-i-propyl](OCH₃), —P(O)[—OCH(CH₃)OC(O)-t-butyl](OCH₃),—P(O)[—OCH(CH₃)OC(O)O-i-propyl](OCH₃), —P(O)[—N(H)CH(CH₃)C(O)OCH₂CH₃](OCH₃), —P(O)[—N(H)CH(CH₃)C(O)OCH₂CH₃](CH₃),—P(O)[—N(H)C(CH₃)₂C(O)OCH₂CH₃](OCH₃),—P(O)[—N(H)C(CH₃)₂C(O)OCH₂CH₃](CH₃), —P(O)[—OCH₂OC(O)-t-butyl](CH₃),—P(O)[—OCH₂OC(O)O-i-propyl](CH₃), —P(O)[—OCH(CH₃)OC(O)-t-butyl](CH₃),—P(O)[—OCH(CH₃)OC(O)O-i-propyl](CH₃), and —P(O)[—OCH₂OC(O)O-ethyl]₂.

A further embodiment (“Embodiment 13”) is the compound of embodiment 1,wherein Y and Y¹ are each independently selected from —O— and —NR⁶⁰—;and together R⁵¹ and R⁵¹ are the group

wherein, V is substituted aryl or substituted heteroaryl,

A further embodiment (“Embodiment 14”) is the compound of embodiment 1,wherein said compound has one of the following combinations ofsubstituents:

Combination No. Substituent No. #1 1, 2 #2 1, 3 #3 1, 4 #4 1, 5 #5 2, 3#6 2, 4 #7 2, 5 #8 3, 4 #9 3, 5 #10 4, 5 #11 1, 2, 3 #12 1, 2, 4 #13 1,2, 5 #14 1, 3, 4 #15 1, 3, 5 #16 1, 4, 5 #17 2, 3, 4 #18 2, 3, 5 #19 2,4, 5 #20 3, 4, 5 #21 1, 2, 3, 4 #22 1, 2, 3, 5 #23 1, 2, 4, 5 #24 1, 3,4, 5 #25 2, 3, 4, 5 #26 1, 2, 3, 4, 5wherein:

any substituent not listed in said combination is as defined inembodiment 1; Substituent 1 is X and:

X is selected from the group consisting of aryl, heteroaryl, alkyl,cycloalkyl, arylalkyl, aryloxy, heteroaryloxy, alkyloxy, cycloalkyloxyand arylalkyloxy; or

X is selected from the group consisting of alkyl, cycloalkyl, alkyloxy,cycloalkyloxy and aryloxy; or

X is selected from the group consisting of alkyloxy and cycloalkyloxy;Substituent 2 is R² and:

R² is selected from the group consisting of aryl, heteroaryl, alkyl,cycloalkyl, arylalkyl, aryloxy, heteroaryloxy, alkyloxy, cycloalkyloxy,arylalkyloxy, arylthio, heteroarylthio, cycloalkylthio andarylalkylthio; or

R² is -E¹-E²-E³, wherein,

E¹ is a bond, O or S;

E² is a bond or alkylene;

wherein, when both E¹ and E² are a bond, together they form a singlebond;

E³ is optionally substituted —C₁₋₄-alkyl, optionally substituted—C₃₋₈-cycloalkyl or aryl optionally substituted with one or two groupsindependently selected from the group consisting of halogen,—C₁₋₄-alkyl, —S(O)₂R⁵ and —OR⁵;

R⁵ is alkyl or cycloalkyl; or

R² is selected from the group consisting of —C₁₋₄-alkyloxy,—C₃₋₆-cycloalkyloxy, benzyloxy, 2-(2-thienyl)ethyloxy,2-(3-thienyl)ethyloxy, and phenyloxy, each optionally substituted withone or two groups independently selected from the group consisting ofhalogen, —C₁₋₄-alkyl, —S(O)₂C₁₋₄-alkyl, —S(O)₂C₃₋₄-cycloalkyl, or—OC₁₋₄-alkyl; or

R² is selected from the group consisting of n-propyloxy, isopropyloxy,2-methylpropyloxy, cylclopentylmethyloxy, benzyloxy,2-(2-thienyl)ethyloxy, 2-(3-thienyl)ethyloxy, 2-fluorophenylmethyloxy,4-methylsulfonylphenyloxy, 4-ethylsulfonylphenyloxy and4-isopropylsulfonylphenyloxy;

Substituent 3 is D and:

D is selected from heteroarylene or arylene, each optionallysubstituted; or

D is heteroarylene, said heteroarylene comprising a nitrogen ring atomadjacent to a carbon ring atom, wherein said carbon ring atom isconnected to the amide nitrogen atom adjacent to D, and wherein saidheteroarylene has an additional 0 to 3 heteroatoms independentlyselected from O, S or N; or

D is a heteroarylene, optionally substituted with one or two groupsindependently selected from halogen and optionally substitutedC₁₋₄-alkyl; wherein, when said heteroarylene is pyridine-diyl,pyrazole-diyl, pyridaze-diyl or pyramidine-diyl, the ring atom atposition 5 of said heteroarylene is connected to R⁵⁰ and when saidheteroarylene is thiazole-diyl or thiadiazole-diyl, the ring atom atposition 4 of said heteroarylene is connected to R⁵⁰, and n is 0 or 1;

Substituent 4 is G¹, G² and G³ and:

G¹, G² and G³ are CR⁴ or N; and R⁴ is H, halogen or alkyl; or

G¹ is CR⁴; G² is CR⁴; G³ is CR⁴; and R⁴ is H, halogen or alkyl; or

G¹ is CH; G² is CH; and G³ is CH; and

Substituent 5 is R⁵⁰ and:

-   -   R⁵⁰ is —R⁶¹-R⁶², and R⁶² is selected from —P(O)(Y²R⁵¹)R¹, or        —P(O)(YR⁵¹)Y¹R⁵¹;    -   R⁶¹ is selected from null, arylene, heteroarylene,        arylene-alkylene, alkylene-arylene, heteroarylene-alkylene,        alkylene-heteroarylene, alkylene, alkenylene, alkynylene,        alkylene-Q-alkylene, —CONR⁵²-alkylene, —COO-alkylene,        —SO₂NR⁵²-alkylene, arylene-Q-alkylene, alkylene-Q-arylene,        heteroarylene-Q-alkylene, alkylene-Q-heteroarylene, all        optionally substituted;        Q is selected from O, S, SO, SO₂, NR⁵³;        R is selected from the group consisting of hydrogen, optionally        substituted —C₁-C₆-alkyl, —CF₃, —CHF₂, —CH₂F, —CH₂OH, optionally        substituted —C₂-C₆ alkenyl, optionally substituted —C₂-C₆        alkynyl, optionally substituted —(CR⁵² ₂)_(n)cycloalkyl,        optionally substituted (CR⁵² ₂)_(n)heterocycloalkyl, —(CR⁵²        ₂)_(k) S(═O)R⁵³, —(CR⁵² ₂)_(k)S(═O)₂R⁵³;

Y, Y¹ and Y² are each independently selected from —O— or —NR⁶⁰—;

wherein,

when Y² is —O— or when Y and Y¹ are both —O—, R⁵¹ attached to —O— isindependently selected from from the group consisting of —H, alkyl,optionally substituted aryl, optionally substituted heterocycloalkyl,optionally substituted —CH₂-heterocycloakyl with a cyclic moietycontaining a carbonate or thiocarbonate, optionally

substituted -alkylaryl, —C(R⁵²)₂OC(O)NR⁵² ₂, —NR⁵²—C(O)—R⁵³,—C(R⁵²)₂—OC(O)R⁵³, —C(R⁵²)₂—O—C(O)OR⁵³, —C(R⁵²)₂OC(O)SR⁵³,-alkyl-S—C(O)R⁵³, -alkyl-S—S-alkylhydroxyand -alkyl-S—S—S-alkylhydroxy; or

when Y² is —NR⁶⁰— or when Y and Y¹ are both —NR⁶⁰—, then R⁵¹ attached to—NR⁶⁰— is independently selected from the group consisting

of —H, —[C(R⁵²)₂]_(r)—COOR⁵³, —C(R⁵⁴)₂COOR⁵³, —[C(R⁵²)₂]_(r)—C(O)SR⁵³,and -cycloalkylene-COOR⁵³; or

when Y is —O— and Y¹ is NR⁶⁰, then R⁵¹ attached to —O— is independentlyselected from —H, alkyl, optionally substituted aryl, optionallysubstituted heterocycloalkyl, optionally substituted CH₂-heterocycloakylwherein the cyclic moiety contains a carbonate or thiocarbonate,optionally

substituted -alkylaryl, —C(R⁵²)₂OC(O)NR⁵² ₂, —NR⁵²—C(O)—R⁵³,—C(R⁵²)₂—OC(O)R⁵³, —C(R⁵²)₂—O—C(O)OR⁵³, —C(R⁵²)₂OC(O)SR⁵³,-alkyl-S—C(O)R⁵³, -alkyl-S—S-alkylhydroxy,and -alkyl-S—S—S-alkylhydroxy, and R⁵¹ attached to —NR⁶⁰— isindependently selected from —H, —[C(R⁵²)₂]_(r)—COOR⁵³, —C(R⁵⁴)₂COOR⁵³,—[C(R⁵²)₂]_(r)—C(O)SR⁵³,and -cycloalkylene-COOR⁵³, wherein if both R⁵¹ are alkyl, at least oneis higher alkyl; or

when Y and Y¹ are independently selected from —O— and —NR⁶⁰—, then R⁵¹and R⁵¹ together form a cyclic group comprising -alkyl-S—S-alkyl-, orR⁵¹ and R⁵¹ together are the group

wherein,

V, W, and W′ are independently selected from the group consisting ofhydrogen, optionally substituted alkyl, optionally substituted aralkyl,heterocycloalkyl, aryl, substituted aryl, heteroaryl, substitutedheteroaryl, optionally substituted 1-alkenyl, and optionally substituted1-alkynyl, and

Z is —CHR⁵²OH, —CHR⁵²OC(O)R⁵³, —CHR⁵²OC(S)R⁵³, —CHR⁵²OC(S)OR⁵³,—CHR⁵²OC(O)SR⁵³, —CHR⁵²OCO₂R⁵³, —OR⁵², —SR⁵², —CHR⁵²N₃, —CH₂aryl,—CH(aryl)OH, —CH(CH═CR⁵² ₂)OH, —CH(C≡CR⁵²)OH, —R⁵², —NR⁵² ₂, —O COR⁵³,—OCO₂R⁵³, —SCOR⁵³, —SCO₂R⁵³, —NHCOR⁵², —NHCO₂R⁵³, —CH₂NHaryl,—(CH₂)_(r)—OR⁵² or —(CH₂)_(r)—SR⁵²; or

W and W′ are as defined above and together V and Z are connected via anadditional 3-5 atoms to form a cyclic group containing 5-7 atoms,wherein 0-1 atoms are heteroatoms and the remaining atoms are carbon; or

W′ and Z are as defined above and together V and W are connected via anadditional 3 carbon atoms to form an optionally substituted cyclic groupcontaining 6 carbon atoms or carbon substituted by hydrogen andsubstituted with one substituent selected from hydroxy, acyloxy,alkoxycarbonyloxy, alkylthiocarbonyloxy or aryloxycarbonyloxy which isattached to one of said carbon atoms that is three atoms from a Yattached to the phosphorus; or

V and W′ are as defined above and together Z and W are connected via anadditional 3-5 atoms to form a cyclic group, wherein 0-1 atoms areheteroatoms and the remaining atoms are carbon or carbon substituted byhydrogen, and V must be aryl, substituted aryl, heteroaryl, orsubstituted heteroaryl; or

V and Z are as defined above and together W and W′ are connected via anadditional 2-5 atoms to form a cyclic group, wherein 0-2 atoms areheteroatoms and the remaining atoms are carbon, where V must be aryl,substituted aryl, heteroaryl, or substituted heteroaryl;

R⁵² is R⁵³ or —H;

R⁵³ is alkyl, aryl, heterocycloalkyl or aralkyl;

R⁵⁴ is independently selected from —H or alkyl, or together R⁵⁴ and R⁵⁴form a cycloalkylene group;

R⁶⁰ is —H, lower alkyl, acyloxyalkyl, alkoxycarbonyloxyalkyl, loweracyl, C₁₋₆-perfluoroalkyl or NH(CR⁵⁵R⁵⁵)_(f)CH₃;

r is an integer 2 or 3;

f is an integer 0, 1 or 2;

wherein, V, Z, W, W′ are not all —H, and when Z is —R⁵², then at leastone of V, W, and W′ is not —H, alkyl, aralkyl, or heterocycloalkyl; or

R⁶² is selected from the group consisting of:

—PO₃H₂, —P(O)[—OCR⁵² ₂OC(O)R⁵³]₂, —P(O)[—OCR⁵² ₂OC(O)OR⁵³]₂,—P(O)[—N(H)CR⁵² ₂C(O)O R⁵³]₂, —P(O)[—O-alk-SC(O)R⁵³]₂, —P(O)[—OCR⁵²₂OC(O)R⁵³][—R¹], —P(O)[—OCR⁵² ₂OC(O)OR⁵³][—R¹], —P(O)[—N(H)CR⁵²₂C(O)OR][—R¹], —P(O)[—OCH₂CH₂SC(O)R⁵³][—R¹], —P(O)(OH)(YR⁵¹),—P(O)(OR⁵⁶)(OR⁵⁶), —P(O)(OH)(—R¹), —P(O)[—OCR⁵² ₂OC(O)R⁵³](OR⁵⁶),—P(O)[—OCR⁵² ₂OC(O)OR⁵³](OR⁵³), —P(O)[—N(H)CR⁵² ₂ C(O)OR⁵³](OR⁵⁶),P(O)(OH)(NH₂), and —P(O)[—OCH(V)CH₂CH₂O—];

V is optionally substituted aryl or optionally substituted heteroaryl;

R⁵⁶ is —C₁-C₁₂ alkyl, —C₂-C₁₂ alkenyl, —C₂-C₁₂ alkynyl, —(CR⁵⁷₂)_(n)aryl, —(CR⁵⁷ ₂)_(n)cycloalkyl, or —(CR⁵⁷ ₂)_(n)heterocycloalkyl,each optionally substituted;

each R⁵⁷ is independently selected from the group consisting ofhydrogen, optionally substituted —C₁-C₄ alkyl, halogen, optionallysubstituted —O—C₁-C₄ alkyl, —OCF₃, optionally substituted —S—C₁-C₄alkyl, —NR⁵⁸R⁵⁹, optionally substituted —C₂-C₄ alkenyl, and optionallysubstituted —C₂-C₄ alkynyl; with the proviso that when one R⁵⁷ isattached to C through an O, S, or N atom, then the other R⁵⁷ attached tothe same C is a hydrogen, or attached via a carbon atom;

R⁵⁸ is selected from hydrogen and optionally substituted —C₁-C₄ alkyl;and,

R⁵⁹ is selected from the group consisting of hydrogen and optionallysubstituted —C₁-C₄ alkyl, optionally substituted —C(O)—C₁-C₄ alkyl and—C(O)H; or

R⁶² is selected from the group consisting of —P(O)(OH)₂,—P(O)[—OCH₂OC(O)-t-butyl]₂, —P(O)[—OCH(CH₃)OC(O)-t-butyl]₂,—P(O)[—OCH(CH₃)OC(O)O-i-propyl]₂, —P(O)[—OCH₂OC(O)O-i-propyl]₂,—P(O)[—N(H)CH(CH₃)C(O)OCH₂CH₃]₂, —P(O)[—N(H)C(CH₃)₂C(O)OCH₂CH₃]₂,—P(O)[—N(H)CH(CH₃)C(O)OCH₂CH₃][3,4-methylenedioxyphenyl],—P(O)[—N(H)C(CH₃)₂C(O)OCH₂CH₃][3,4-methylenedioxyphenyl],—P(O)[—O—CH₂CH₂S—C(O)CH₃]₂, —P(O)(OH)(OCH₃), —P(O)(OH)(OCH₂CH₃),—P(O)(OH)(CH₃), —P(O)[—OCH(3-chlorophenyl)CH₂CH₂O—],—P(O)[—OCH(pyrid-4-yl)CH₂CH₂O—], —P(O)[—OCH₂OC(O)-i-butyl](OCH₃),—P(O)[—OCH₂OC(O)O-i-propyl](OCH₃), —P(O)[—OCH(CH₃)OC(O)-t-butyl](OCH₃),—P(O)[—OCH(CH₃)OC(O)O-i-propyl](OCH₃), —P(O)[—N(H)CH(CH₃)C(O)OCH₂CH₃](OCH₃), —P(O)[—N(H)CH(CH₃)C(O)OCH₂CH₃](CH₃),—P(O)[—N(H)C(CH₃)₂C(O)OCH₂CH₃](OCH₃),—P(O)[—N(H)C(CH₃)₂C(O)OCH₂CH₃](CH₃), —P(O) [—OCH₂OC(O)-t-butyl](CH₃),—P(O)[—OCH₂OC(O)O-i-propyl](CH₃), —P(O)[—OCH(CH₃)OC(O)-t-butyl](CH₃),—P(O)[—OCH(CH₃)OC(O)O-i-propyl](CH₃),

and —P(O)[—OCH₂OC(O)O-ethyl]₂.

A further embodiment (“Embodiment 15”) is the compound of embodiment 14,wherein:

Substituent 1 is X and:

X is selected from the group consisting of aryl, heteroaryl, alkyl,cycloalkyl, arylalkyl, aryloxy, heteroaryloxy, alkyloxy, cycloalkyloxyand arylalkyloxy;

Substituent 2 is R² and:

R² is selected from the group consisting of aryl, heteroaryl, alkyl,cycloalkyl, arylalkyl, aryloxy, heteroaryloxy, alkyloxy, cycloalkyloxy,arylalkyloxy, arylthio, heteroarylthio, cycloalkylthio andarylalkylthio;

Substituent 3 is D and:

D is selected from heteroarylene or arylene, each optionallysubstituted;

Substituent 4 is G¹, G² and G³ and:

G¹, G² and G³ are CR⁴ or N; and R⁴ is H, halogen or alkyl;

Substituent 5 is R⁵⁰ and:

-   -   R⁵⁰ is —R⁶¹-R⁶², and R⁶² is selected from —P(O)(Y²R⁵¹)R¹, or        —P(O)(YR⁵¹)Y¹R¹;    -   R⁶¹ is selected from null, arylene, heteroarylene,        arylene-alkylene, alkylene-arylene, heteroarylene-alkylene,        alkylene-heteroarylene, alkylene, alkenylene, alkynylene,        alkylene-Q-alkylene, —CONR⁵²-alkylene, —COO-alkylene,        —SO₂NR⁵²-alkylene, arylene-Q-alkylene, alkylene-Q-arylene,        heteroarylene-Q-alkylene, alkylene-Q-heteroarylene, all        optionally substituted;    -   Q is selected from O, S, SO, SO₂, NR⁵³;        -   R¹ is selected from the group consisting of hydrogen,            optionally substituted —C₁-C₆-alkyl, —CF₃, —CHF₂, —CH₂F,            —CH₂OH, optionally substituted —C₂-C₆ alkenyl, optionally            substituted —C₂-C₆ alkynyl, optionally substituted —(CR⁵²            ₂), cycloalkyl, optionally substituted (CR⁵²            ₂)_(n)heterocycloalkyl, —(CR⁵² ₂)_(k) S(═O)R⁵³, —(CR⁵²            ₂)_(k)S(═O)₂R⁵³;            Y, Y¹ and Y² are each independently selected from —O— or            —NR⁶⁰—;

wherein,

when Y² is —O— or when Y and Y¹ are both —O—, R⁵¹ attached to —O— isindependently selected from the group consisting of —H, alkyl,optionally substituted aryl, optionally substituted heterocycloalkyl,optionally substituted —CH₂-heterocycloakyl with a cyclic moietycontaining a carbonate or thiocarbonate, optionally

substituted -alkylaryl, —C(R⁵²)₂OC(O)NR⁵² ₂, —NR⁵²—C(O)—R⁵³,—C(R⁵²)₂—OC(O)R⁵³, —C(R⁵²)²—O—C(O)OR⁵³, —C(R⁵²)₂OC(O)SR⁵³,-alkyl-S—C(O)R⁵³, -alkyl-S—S-alkylhydroxyand -alkyl-S—S—S-alkylhydroxy; or

when Y² is —NR⁶⁰— or when Y and Y¹ are both —NR⁶⁰—, then R⁵¹ attached to—NR⁶⁰— is independently selected from the group consisting of —H,—[C(R⁵²)₂]_(r)—COOR⁵³, —C(R⁵⁴)₂COOR⁵³, —[C(R⁵²)₂]_(r)—C(O)SR⁵³,

and -cycloalkylene-COOR⁵³; or

when Y is —O— and Y¹ is NR⁶⁰, then R⁵¹ attached to —O— is independentlyselected from —H, alkyl, optionally substituted aryl, optionallysubstituted heterocycloalkyl, optionally substituted CH₂-heterocycloakylwherein the cyclic moiety contains a carbonate or thiocarbonate,optionally substituted -alkylaryl, —C(R⁵²)₂OC(O)NR⁵² ₂, —NR⁵²—C(O)—R⁵³,—C(R⁵²)₂—OC(O)R⁵³, —C(R⁵²)₂—O—C(O)OR⁵³, —C(R⁵²)₂OC(O)SR⁵³,-alkyl-S—C(O)R⁵³, -alkyl-S—S-alkylhydroxy, and-alkyl-S—S—S-alkylhydroxy, and R⁵¹ attached to —NR⁶⁰— is independentlyselected from —H, —[C(R⁵²)₂]_(r)—COOR⁵³, —C(R⁵⁴)₂COOR⁵³,—[C(R⁵²)₂]_(r)—C(O)SR⁵³, and -cycloalkylene-COOR⁵³, wherein if both R⁵¹are alkyl, at least one is higher alkyl; or

when Y and Y¹ are independently selected from —O— and —NR⁶⁰—, then R⁵¹and R⁵¹ together form a cyclic group comprising -alkyl-S—S-alkyl-, orR⁵¹ and R⁵¹ together are the group

wherein,

V, W, and W′ are independently selected from the group consisting ofhydrogen, optionally substituted alkyl, optionally substituted aralkyl,heterocycloalkyl, aryl, substituted aryl, heteroaryl, substitutedheteroaryl, optionally substituted 1-alkenyl, and optionally substituted1-alkynyl, and

Z is —CHR⁵²OH, —CHR⁵²OC(O)R⁵³, —CHR⁵²OC(S)R⁵³, —CHR⁵²OC(S)OR⁵³,—CHR⁵²OC(O)SR⁵³, —CHR⁵²OCO₂R⁵³, —OR⁵², —SR⁵², —CHR⁵²N₃, —CH₂aryl,—CH(aryl)OH, —CH(CH═CR⁵² ₂)OH, —CH(C≡CR⁵²)OH, —R⁵², —NR⁵² ₂, —O COR⁵³,—OCO₂R⁵³, —SCOR⁵³, —SCO₂R⁵³, —NHCOR⁵², —NHCO₂R⁵³, —CH₂NHaryl,—(CH₂)_(r)—OR⁵² or —(CH₂)_(r)—SR⁵²; or

W and W′ are as defined above and together V and Z are connected via anadditional 3-5 atoms to form a cyclic group containing 5-7 atoms,wherein 0-1 atoms are heteroatoms and the remaining atoms are carbon; or

W′ and Z are as defined above and together V and W are connected via anadditional 3 carbon atoms to form an optionally substituted cyclic groupcontaining 6 carbon atoms or carbon substituted by hydrogen andsubstituted with one substituent selected from hydroxy, acyloxy,alkoxycarbonyloxy, alkylthiocarbonyloxy or aryloxycarbonyloxy which isattached to one of said carbon atoms that is three atoms from a Yattached to the phosphorus; or

V and W′ are as defined above and together Z and W are connected via anadditional 3-5 atoms to form a cyclic group, wherein 0-1 atoms areheteroatoms and the remaining atoms are carbon or carbon substituted byhydrogen, and V must be aryl, substituted aryl, heteroaryl, orsubstituted heteroaryl; or

V and Z are as defined above and together W and W′ are connected via anadditional 2-5 atoms to form a cyclic group, wherein 0-2 atoms areheteroatoms and the remaining atoms are carbon, where V must be aryl,substituted aryl, heteroaryl, or substituted heteroaryl;

R⁵¹ is R⁵³ or —H;

R⁵³ is alkyl, aryl, heterocycloalkyl or aralkyl;

R⁵⁴ is independently selected from —H or alkyl, or together R⁵⁴ and R⁵⁴form a cycloalkylene group;

R⁶⁰ is —H, lower alkyl, acyloxyalkyl, alkoxycarbonyloxyalkyl, loweracyl, C₁₋₆-perfluoroalkyl or NH(CR⁵⁵R⁵⁵)_(f)CH₃;

r is an integer 2 or 3;

f is an integer 0, 1 or 2;

-   -   wherein, V, Z, W, W′ are not all —H, and when Z is —R⁵², then at        least one of V, W, and W′ is not —H, alkyl, aralkyl, or        heterocycloalkyl,

A further embodiment (“Embodiment 16”) is the compound of embodiment 14,wherein:

Substituent 1 is X and:

X is selected from the group consisting of alkyl, cycloalkyl, alkyloxy,cycloalkyloxy and aryloxy;

Substituent 2 is R² and:

R² is -E¹-E²-E³, wherein,

E¹ is a bond, O or S;

E² is a bond or alkylene;

wherein, when both E¹ and E² are a bond, together they form a singlebond;

E³ is optionally substituted —C₁₋₄-alkyl, optionally substituted—C₃₋₈-cycloalkyl or aryl optionally substituted with one or two groupsindependently selected from the group consisting of halogen,—C₁₋₄-alkyl, —S(O)₂R⁵ or —OR⁵;

R⁵ is alkyl or cycloalkyl; or

R² is selected from the group consisting of —C₁₋₄-alkyloxy,—C₃₋₆-cycloalkyloxy, benzyloxy, 2-(2-thienyl)ethyloxy,2-(3-thienyl)ethyloxy, and phenyloxy, each optionally substituted withone or two groups independently selected from the group consisting ofhalogen, —C₁₋₄-alkyl, —S(O)₂C₁₋₄-alkyl, —S(O)₂C₃₋₆-cycloalkyl, or—OC₁₋₄-alkyl;

Substituent 3 is D and:

D is heteroarylene, alkylene-heteroarylene, or arylene-heteroarylene,said heteroarylene comprising a nitrogen ring atom adjacent to a carbonring atom, wherein said carbon ring atom is connected to the amidenitrogen atom adjacent to D, and wherein said heteroarylene has anadditional 0 to 3 heteroatoms independently selected from O, S or N;

Substituent 4 is G¹, G² and G³ and:

G¹ is CR⁴; G² is CR⁴; G³ is CR⁴; and R⁴ is H, halogen or alkyl; and

Substituent 5 is R⁶² and:

R⁶² is selected from the group consisting of

—PO₃H₂, —P(O)[—OCR⁵² ₂OC(O)R⁵³]₂, —P(O)[—OCR⁵² ₂OC(O)OR⁵³]₂,—P(O)[—N(H)CR⁵² ₂C(O)O R⁵³]₂, —P(O)[—O-alk-SC(O)R⁵³]₂, —P(O)[—OCR⁵²₂OC(O)R⁵³][—R¹], —P(O)[—OCR⁵² ₂OC(O)OR⁵³][—R¹], —P(O)[—N(H)CR⁵²₂C(O)OR⁵³][—R¹], —P(O)[—OCH₂CH₂SC(O)R⁵³][—R¹], —P(O)(OH)(YR⁵¹),—P(O)(OR⁵⁶)(OR⁵⁶), —P(O)(OH)(—R¹), —P(O)[—OCR⁵² ₂OC(O)R⁵³](OR⁵⁶),—P(O)[—OCR⁵² ₂OC(O)OR⁵³](OR⁵⁶), —P(O)[—N(H)CR⁵² ₂ C(O)OR⁵³](OR⁵⁶),P(O)(OH)(NH₂), and —P(O)[—OCH(V)CH₂CH₂O—];

V is optionally substituted aryl or optionally substituted heteroaryl;

R⁵⁶ is —C₁-C₁₂ alkyl, —C₂-C₁₂ alkenyl, —C₂-C₁₂ alkynyl, —(CR⁵⁷ ₂)aryl,—(CR⁵⁷ ₂)cycloalkyl, or —(CR⁵⁷ ₂)heterocycloalkyl, each optionallysubstituted;

each R⁵⁷ is independently selected from the group consisting ofhydrogen, optionally substituted —C₁-C₄ alkyl, halogen, optionallysubstituted —O—C₁-C₄ alkyl, —OCF₃, optionally substituted —S—C₁-C₄alkyl, —NR⁵⁸R⁵⁹, optionally substituted —C₂-C₄ alkenyl, and optionallysubstituted —C₂-C₄ alkynyl; with the proviso that when one R⁵⁷ isattached to C through an O, S, or N atom, then the other R⁵⁷ attached tothe same C is a hydrogen, or attached via a carbon atom;

R⁵⁸ is selected from hydrogen and optionally substituted —C₁-C₄ alkyl;and,

R⁵⁹ is selected from the group consisting of hydrogen and optionallysubstituted —C₁-C₄ alkyl, optionally substituted —C(O)—C₁-C₄ alkyl and—C(O)H.

A further embodiment (“Embodiment 17”) is the compound of embodiment 14,wherein:

Substituent 1 is X and:

X is selected from the group consisting of alkyloxy and cycloalkyloxy;

Substituent 2 is R² and:

R² is selected from the group consisting of —C₁₋₄-alkyloxy,—C₃₋₆-cycloalkyloxy, benzyloxy, 2-(2-thienyl)ethyloxy,2-(3-thienyl)ethyloxy, and phenyloxy, each optionally substituted withone or two groups independently selected from the group consisting ofhalogen, —C₁₋₄-alkyl, —S(O)₂C₁₋₄-alkyl, —S(O)₂C₃₋₆-cycloalkyl, or—OC₁₋₄-alkyl; or

Substituent 3 is D and:

D is a heteroarylene, optionally substituted with one or two groupsindependently selected from halogen and optionally substitutedC₁₋₄-alkyl; wherein, when said heteroarylene is pyridine-diyl,pyrazole-diyl, pyridaze-diyl or pyramidine-diyl, the ring atom atposition 5 of said heteroarylene is connected to R⁵⁰ and when saidheteroarylene is thiazole-diyl or thiadiazole-diyl, the ring atom atposition 4 of said heteroarylene is connected to R⁵⁰, and n is 0 or 1;

Substituent 4 is G¹, G² and G³ and:

G¹ is CH; G² is CH; and G³ is CH; and

Substituent 5 is R⁵² and:

R⁶ is selected from the group consisting of —P(O)(OH)₂,—P(O)[—OCH₂OC(O)-t-butyl]₂, —P(O)[—OCH(CH₃)OC(O)-t-butyl]₂,—P(O)[—OCH(CH₃)OC(O)O-i-propyl]₂, —P(O)[—OCH₂OC(O)O-i-propyl],—P(O)[—N(H)CH(CH₃)C(O)OCH₂ CH₃]₂, —P(O)[—N(H)C(CH₃)₂C(O)OCH₂CH₃]₂,—P(O)[—N(H)CH(CH₃)C(O)OCH₂CH₃][3,4-methylenedioxyphenyl],—P(O)[—N(H)C(CH₃)₂C(O)OCH₂CH₃][3,4-methylenedioxyphenyl],—P(O)[—O—CH₂CH₂S—C(O)CH₃]₂, —P(O)(OH)(OCH₃), —P(O)(OH)(OCH₂CH₃),—P(O)(OH)(CH₃), —P(O)[—OCH(3-chlorophenyl)CH₂CH₂O—],—P(O)[—OCH(pyrid-4-yl)CH₂CH₂O—], —P(O)[—OCH₂OC(O)-t-butyl](OCH₃),—P(O)[—OCH₂OC(O)O-i-propyl](OCH₃), —P(O)[—OCH(CH₃)OC(O)-t-butyl](OCH₃),—P(O)[—OCH(CH₃)OC(O)O-i-propyl](OCH₃), —P(O)[—N(H)CH(CH₃)C(O)OCH₂CH₃](OCH₃), —P(O)[—N(H)CH(CH₃)C(O)OCH₂CH₃](CH₃),—P(O)[—N(H)C(CH₃)₂C(O)OCH₂CH₃](OCH₃),—P(O)[—N(H)C(CH₃)₂C(O)OCH₂CH₃](CH₃), —P(O) [—OCH₂OC(O)-t-butyl](CH₃),—P(O)[—OCH₂OC(O)O-i-propyl](CH₃), —P(O)[—OCH(CH₃)OC(O)-t-butyl](CH₃),—P(O)[—OCH(CH₃)OC(O)O-i-propyl](CH₃),

and —P(O)[—OCH₂OC(O)O-ethyl]₂

A further embodiment (“Embodiment 18”) is the compound of embodiments14, 15, 16 or 17, wherein R² is selected from the group consisting ofn-propyloxy, isopropyloxy, 2-methylpropyloxy, cylclopentylmethyloxy,benzyloxy, 2-(2-thienyl)ethyloxy, 2-(3-thienyl)ethyloxy,2-fluorophenylmethyloxy, 4-methylsulfonylphenyloxy,4-ethylsulfonylphenyloxy and 4-isopropylsulfonylphenyloxy.

A further embodiment (“Embodiment 19”) is the compound according to anyof embodiments 1-18, wherein R⁶¹ is selected from null, arylene,heteroarylene, arylene-alkylene, alkylene-arylene,heteroarylene-alkylene, alkylene-heteroarylene, —CONR⁵²-alkylene,—COO-alkylene or —SO₂NR⁵²-alkylene, and all groups are optionallysubstituted.

A further embodiment (“Embodiment 20”) is the compound according to anyof embodiments 1-18, wherein R⁶¹ is selected from null, arylene,heteroarylene, and all groups are optionally substituted.

A further embodiment (“Embodiment 21”) is a compound of general Formula(11),

wherein:

X is selected from the group consisting of aryl, heteroaryl, alkyl,cycloalkyl, arylalkyl, aryloxy, heteroaryloxy, alkyloxy, cycloalkyloxyand arylalkyloxy, and

G² is CR⁴ or N, or

together G² and X are connected to form a cyclic group containing 5-7atoms, wherein 0-2 atoms of said cyclic group are heteroatoms and theremaining atoms of said cyclic group are carbon atoms substituted withalkyl, aryl, cycloalkyl or heteroaryl;

R² is optionally substituted and is selected from arylene,heteroarylene, alkylene, cycloalkylene, arylalkylene, alkylarylene,arylene-O—, heteroarylene-O—, alkylene-O—, cycloalkylene-O—,arylalkylene-O—, alkylarylene-O—, arylene-S—, heteroarylene-S—,alkylene-S-cycloalkylene-S—, arylalkylene-S—, or alkylarylene-S—,wherein R² is connected to R⁵⁰ by a C atom;

G¹ is CR⁴ or N;

R⁴ is H, halogen or optionally substituted alkyl;

G³ is CR⁴ or N;

R⁴ is H, halogen or optionally substituted alkyl;

D is selected from a group consisting of heteroaryl or aryl;

R⁵⁰ is —P(O)(Y²R⁵¹) R¹ or —P(O)(YR⁵¹)Y¹R⁵¹;

R¹ is selected from the group consisting of hydrogen, optionallysubstituted —C₁-C₆-alkyl, —CF₃, —CHF₂, —CH₂F, —CH₂OH, optionallysubstituted —C₂-C₆ alkenyl, optionally substituted —C₂-C₆ alkynyl,optionally substituted —(CR⁵² ₂)_(n)cycloalkyl, optionally substituted(CR⁵² ₂)_(n)heterocycloalkyl, —(CR⁵² ₂)_(k) S(═O)R⁵³, —(CR⁵²₂)_(k)S(═O)₂R⁵³;

Y, Y¹ and Y² are each independently selected from —O— or —NR⁶⁰—;

wherein,

when Y² is —O— or when Y and Y¹ are both —O—, R⁵¹ attached to —O— isindependently selected from —H, alkyl, optionally substituted aryl,optionally substituted heterocycloalkyl, optionally substituted—CH₂-heterocycloakyl wherein the cyclic moiety contains a carbonate orthiocarbonate, optionally

substituted -alkylaryl, —C(R⁵²)₂OC(O)NR⁵² ₂, —NR⁵²—C(O)—R⁵³,—C(R⁵²)₂—OC(O)R⁵³, —C(R⁵²)₂—O—C(O)OR⁵³, —C(R⁵²)₂OC(O)SR⁵³,-alkyl-S—C(O)R⁵³, -alkyl-S—S-alkylhydroxy,and -alkyl-S—S—S-alkylhydroxy; or

when Y² is —NR⁶⁰— or when Y and Y¹ are both —NR⁶⁰— then R⁵¹ attached to—NR⁶⁰— is independently selected from —H, —[C(R⁵²)₂]_(r)—COOR⁵³,—C(R⁵⁴)COOR⁵³, —[C(R⁵²)₂]_(r)—C(O)SR⁵³, and -cycloalkylene-COOR⁵³; or

when Y is —O— and Y¹ is NR⁶⁰, then R⁵¹ attached to —O— is independentlyselected from —H, alkyl, optionally substituted aryl, optionallysubstituted heterocycloalkyl, optionally substituted CH₂-heterocycloakylwherein the cyclic moiety contains a carbonate or thiocarbonate,optionally substituted -alkylaryl, —C(R⁵²)₂OC(O)NR⁵² ₂, —NR⁵²—C(O)—R⁵³,—C(R⁵²)₂—OC(O)R⁵³, —C(R⁵²)₂—O—C(O)OR⁵³, —C(R⁵²)₂OC(O)SR⁵³,-alkyl-S—C(O)R⁵³, -alkyl-S—S-alkylhydroxy, and-alkyl-S—S—S-alkylhydroxy, and R⁵¹ attached to —NR⁶⁰— is independentlyselected from —H, —[C(R⁵²)₂]_(r)—COOR⁵³, —C(R⁵⁴)₂COOR⁵³,—[C(R⁵²)₂]_(r)C(O)SR⁵³, and -cycloalkylene-COOR⁵³, wherein if both R⁵¹are alkyl, at least one is higher alkyl; or

when Y and Y¹ are independently selected from —O— and —NR⁶⁰—, then R⁵¹and R⁵¹ together form a cyclic group comprising -alkyl-S—S-alkyl-, orR⁵¹ and R⁵¹ together are the group

wherein,

V, W, and W′ are independently selected from the group consisting ofhydrogen, optionally substituted alkyl, optionally substituted aralkyl,heterocycloalkyl, aryl, substituted aryl, heteroaryl, substitutedheteroaryl, optionally substituted 1-alkenyl, and optionally substituted1-alkynyl, and

Z is —CHR⁵²OH, —CHR⁵²OC(O)R⁵³, —CHR⁵²OC(S)R⁵³, —CHR⁵²OC(S)OR⁵³,—CHR⁵²OC(O)SR⁵³, —CHR⁵²OCO₂R⁵³, —OR⁵², —SR⁵², —CHR⁵²N₃,—CH₂aryl,—CH(aryl)OH, —CH(CH═CR⁵² ₂)OH, —CH(C≡CR⁵²)OH, —R⁵², —NR⁵² ₂, —OC OR⁵³,—OCO₂R⁵³, —SCOR⁵³, —SCO₂R⁵³, —NHCOR⁵², —NHCO₂R⁵³, —CH₂NHaryl,—(CH₂)_(r)—OR⁵² or —(CH₂)_(r)—SR⁵²; or

W and W are as defined above and together V and Z are connected via anadditional 3-5 atoms to form a cyclic group containing 5-7 atoms,wherein 0-1 atoms are heteroatoms and the remaining atoms are carbon; or

W′ and Z are as defined above and together V and W are connected via anadditional 3 carbon atoms to form an optionally substituted cyclic groupcontaining 6 carbon atoms or carbon substituted by hydrogen andsubstituted with one substituent selected from hydroxy, acyloxy,alkoxycarbonyloxy, alkylthiocarbonyloxy or aryloxycarbonyloxy which isattached to one of said carbon atoms that is three atoms from a Yattached to the phosphorus; or

V and W′ are as defined above and together 7 and W are connected via anadditional 3-5 atoms to form a cyclic group, wherein 0-1 atoms areheteroatoms and the remaining atoms are carbon or carbon substituted byhydrogen, and V must be aryl, substituted aryl, heteroaryl, orsubstituted heteroaryl; or

V and Z are as defined above and together W and W′ are connected via anadditional 2-5 atoms to form a cyclic group, wherein 0-2 atoms areheteroatoms and the remaining atoms are carbon, where V must be aryl,substituted aryl, heteroaryl, or substituted heteroaryl;

R⁵² is R⁵³ or —H;

R⁵³ is alkyl, aryl, heterocycloalkyl or aralkyl;

R⁵⁴ is independently selected from —H or alkyl, or together R⁵⁴ and R⁵⁴form a cycloalkylene group;

R⁶⁰ is —H, lower alkyl, acyloxyalkyl, alkoxycarbonyloxyalkyl, loweracyl, C₁₋₆-perfluoroalkyl or NH(CR⁵³R⁵⁵)_(f)CH₃;

r is an integer 2 or 3;

f is an integer 0, i or 2;

wherein, V, Z, W, W′ are not all —H, and when Z is —R⁵², then at leastone of V, W, and W′ is not —H, alkyl, aralkyl, or heterocycloalkyl; and

pharmaceutically acceptable salts, co-crystals and prodrugs thereof.

A further embodiment (“Embodiment 22”) is the compound of embodiment 21,wherein X is selected from the group consisting of alkyl, cycloalkyl,alkyloxy, cycloalkyloxy and aryloxy.

A further embodiment (“Embodiment 23”) is the compound of embodiment 21,wherein X is selected from the group consisting of alkyloxy andcycloalkyloxy.

A further embodiment (“Embodiment 24”) is the compound of embodiment 21,wherein X is selected from the group consisting of aryl, heteroaryl,alkyl, cycloalkyl, arylalkyl, aryloxy, heteroaryloxy, alkyloxy,cycloalkyloxy and arylalkyloxy.

A further embodiment (“Embodiment 25”) is the compound of embodiment 21,wherein R² is -E¹-E²-E³-E⁴-, wherein E⁴ is connected to R⁵⁰;

E¹ is a bond, O or S;

E² is a bond or alkylene;

E³ is optionally substituted C₁₋₄-alkylene, optionally substitutedC₃₋₈-cycloalkylalkylene, arylene or heteroarylene optionally substitutedwith one or two groups independently selected from aryl, heteroaryl,cycloalkyl, cycloalkenyl, halogen, CN, CF₃, NR⁵ ₂, —C₁₋₄-alkyl, —S(O)₂R⁵or —OR⁵; wherein, when both E¹ and E² are a bond, together they form asingle bond;

R⁵ is optionally substituted alkyl or cycloalkyl; and

E⁴ is a bond or alkylene.

A further embodiment (“Embodiment 26”) is the compound of embodiment 21,wherein R² is selected from the group consisting of phenylene-O—,methylene-phenylene-O—, phenylene-methylene-O—, furan-2-yl-5-methylene,thiophen-2-yl-5-methylene, pyridin-diyl-O—, pyrimidin-diyl-O—,pyridazin-diyl-O— and pyrazin-diyl-O—, each optionally substituted withone or two groups independently selected from aryl, heteroaryl, halogen,CN, CF₃, NR⁵ ₂, —C₁₋₄-alkyl, —S(O)₂R⁵ or —OR⁵, wherein R⁵⁰ is connectedto R² by a carbon atom.

A further embodiment (“Embodiment 27”) is the compound of embodiment 21,wherein R² is methylene-thiophen-2,5-diyl, phenylene-O— orthiophen-2-yl-S-methylene, wherein R⁵ is connected to the phenylene orthiophenyl group.

A further embodiment (“Embodiment 28”) is the compound of embodiment 21,wherein R² is optionally substituted and is selected from arylene,heteroarylene, alkylene, cycloalkylene, arylalkylene, alkylarylene,arylene-O—, heteroarylene-O—, alkylene-O—, cycloalkylene-O—,arylalkylene-O—, alkylarylene-O—, arylene-S—, heteroarylene-S—,alkylene-S—, cycloalkylene-S—, arylalkylene-S—, or alkylarylene-S—,wherein R⁵⁰ is connected to R² by a carbon atom.

A further embodiment (“Embodiment 29”) is the compound according toembodiment 21, wherein G¹ and G² are CR⁴ or N.

A further embodiment (“Embodiment 30”) is the compound of embodiment 21,wherein G¹ and G² are CR⁴ and R⁴ is H, halogen or optionally substitutedalkyl.

A further embodiment (“Embodiment 31”) is the compound according toembodiment 30, wherein R⁴ is H.

A further embodiment (“Embodiment 32”) is the compound of embodiment 21,wherein G³ is CR⁴ or N.

A further embodiment (“Embodiment 33”) is the compound of embodiment 21,wherein G³ is CR⁴ and R⁴ is I— halogen or optionally substituted alkyl.

A further embodiment (“Embodiment 34”) is the compound of embodiment 21,wherein R⁴ is H.

A further embodiment (“Embodiment 35”) is the compound of embodiment 21,wherein D is selected from a group consisting of heteroaryl or aryl.

A further embodiment (“Embodiment 36”) is the compound of embodiment 21,wherein D is a heteroaryl having a nitrogen as a ring atom, saidheteroaryl comprising a nitrogen ring atom adjacent to a carbon ringatom, wherein said carbon ring atom is connected to the amide nitrogenatom adjacent to D, and wherein said heteroaryl has an additional 0 to 3heteroatoms independently selected from O, S or N.

A further embodiment (“Embodiment 37”) is the compound of embodiment 21,wherein D is selected from the group consisting of pyridinyl, thiazolyl,1,3,4-thiadiazolyl, 1,2,4-thiadiazolyl, oxazolyl, isoxazolyl,imidazolyl, pyrazolyl, pyrazinyl, pyridazinyl, pyrimidinyl,benzothiazolyl and 5,6-dihydro-4H-cyclopentathiazolyl, each optionallysubstituted with one or two groups selected from halogen, CF₃, oroptionally substituted C₁₋₄-alkyl.

A further embodiment (“Embodiment 38”) is the compound of embodiment 21,wherein D is selected from the group consisting of thiazolyl,1,3,4-thiadiazolyl, and 1,2,4-thiadiazolyl, each optionally substitutedwith one or two groups selected from halogen, CF₃, or optionallysubstituted C₁₋₄-alkyl.

A further embodiment (“Embodiment 39”) is the compound of embodiment 21,wherein R⁵⁰ is —P(O)(Y²R⁵¹) R¹ or —P(O)(YR⁵¹)Y¹R⁵¹;

R¹ is selected from the group consisting of hydrogen, optionallysubstituted —C₁-C₆-alkyl, —CF₃, —CHF₂, —CH₂F, —CH₂OH, optionallysubstituted —C₂-C₆ alkenyl, optionally substituted —C₂-C₆ alkynyl,optionally substituted —(CR⁵² ₂)cycloalkyl, optionally substituted (CR⁵²₂)_(n)heterocycloalkyl, —(CR⁵² ₂)_(k) S(═O)R⁵³, —(CR⁵² ₂)_(k)S(═O)₂R⁵³;

Y, Y¹ and Y² are each independently selected from —O— or —NR⁶⁰—;

wherein,

when Y² is —O— or when Y and Y¹ are both —O—, R⁵¹ attached to —O— isindependently selected from —H, alkyl, optionally substituted aryl,optionally substituted heterocycloalkyl, optionally substituted—CH₂-heterocycloakyl wherein the cyclic moiety contains a carbonate orthiocarbonate, optionally

substituted -alkylaryl, —C(R⁵²)₂OC(O)NR⁵² ₂, —NR⁵²—C(O)—R⁵³,—C(R⁵²)₂—OC(O)R⁵³, —C(R⁵²)₂—O—C(O)OR⁵³, —C(R⁵²)₂OC(O)SR⁵³,-alkyl-S—C(O)R⁵³, -alkyl-S—S-alkylhydroxy,and -alkyl-S—S—S-alkylhydroxy; or

when Y² is —NR⁶⁰— or when Y and Y¹ are both —NR⁶⁰—, then R⁵¹ attached to—NR⁶⁰— is independently selected from —H, —[C(R⁵²)₂]_(r)—COOR⁵³,—C(R⁵⁴)₂COOR⁵³, —[C(R⁵²)₂]_(r)—C(O)SR⁵³, and -cycloalkylene-COOR⁵³; or

when Y is —O— and Y¹ is NR⁶⁰, then R⁵¹ attached to —O— is independentlyselected from —H, alkyl, optionally substituted aryl, optionallysubstituted heterocycloalkyl, optionally substituted CH₂-heterocycloakylwherein the cyclic moiety contains a carbonate or thiocarbonate,optionally substituted -alkylaryl, —C(R⁵²)₂OC(O)NR⁵² ₂, —NR⁵²—C(O)—R⁵³,—C(R⁵²)₂—OC(O)R⁵³, —C(R⁵²)₂—O—C(O)OR⁵³, —C(R⁵²)₂OC(O)SR⁵³,-alkyl-S—C(O)R⁵³, -alkyl-S—S-alkylhydroxy, and-alkyl-S—S—S-alkylhydroxy, and R⁵¹ attached to —NR⁶⁰— is independentlyselected from —H, —[C(R⁵²)₂]_(r)—COOR⁵³, —C(R⁵⁴)₂COOR⁵³,—[C(R⁵²)₂]_(r)—C(O)SR⁵³, and -cycloalkylene-COOR⁵³, wherein if both R⁵¹are alkyl, at least one is higher alkyl; or

when Y and Y¹ are independently selected from —O— and —NR⁶⁰—, then R⁵¹and R⁵¹ together form a cyclic group comprising -alkyl-S—S-alkyl-, orR⁵¹ and R⁵¹ together are the group

wherein,

V, W, and W′ are independently selected from the group consisting ofhydrogen, optionally substituted alkyl, optionally substituted aralkyl,heterocycloalkyl, aryl, substituted aryl, heteroaryl, substitutedheteroaryl, optionally substituted 1-alkenyl, and optionally substituted1-alkynyl, and

Z is —CHR⁵²OH, —CHR⁵²OC(O)R⁵³, —CHR⁵²OC(S)R⁵³, —CHR⁵²OC(S)OR⁵³,—CHR⁵²OC(O)SR⁵³, —CHR⁵²OCO₂R⁵³, —OR⁵², —SR⁵², —CHR⁵²N₃, —CH₂aryl,—CH(aryl)OH, —CH(CH═CR⁵² ₂)OH, —CH(C≡CR⁵²)OH, —R⁵², —NR⁵² ₂, —OC OR⁵³,—OCO₂R⁵³, —SCOR⁵³, —SCO₂R⁵³, —NHCOR⁵², —NHCO₂R⁵³, —CH₂NHaryl,—(CH₂)_(r)—OR⁵² or —(CH₂)—SR⁵²; or

W and W are as defined above and together V and Z are connected via anadditional 3-5 atoms to form a cyclic group containing 5-7 atoms,wherein 0-1 atoms are heteroatoms and the remaining atoms are carbon; or

W′ and Z are as defined above and together V and W are connected via anadditional 3 carbon atoms to form an optionally substituted cyclic groupcontaining 6 carbon atoms or carbon substituted by hydrogen andsubstituted with one substituent selected from hydroxy, acyloxy,alkoxycarbonyloxy, alkylthiocarbonyloxy or aryloxycarbonyloxy which isattached to one of said carbon atoms that is three atoms from a Yattached to the phosphorus; or

V and W′ are as defined above and together Z and W are connected via anadditional 3-5 atoms to form a cyclic group, wherein 0-1 atoms areheteroatoms and the remaining atoms are carbon or carbon substituted byhydrogen, and V must be aryl, substituted aryl, heteroaryl, orsubstituted heteroaryl; or

V and Z are as defined above and together W and W′ are connected via anadditional 2-5 atoms to form a cyclic group, wherein 0-2 atoms areheteroatoms and the remaining atoms are carbon, where V must be aryl,substituted aryl, heteroaryl, or substituted heteroaryl;

R⁵² is R⁵³ or —H:

R⁵³ is alkyl, aryl, heterocycloalkyl or aralkyl;

R⁵⁴ is independently selected from —H or alkyl, or together R⁵⁴ and R⁵⁴form a cycloalkylene group;

R⁶⁰ is —H, lower alkyl, acyloxyalkyl, alkoxycarbonyloxyalkyl, loweracyl, C₁₋₆-perfluoroalkyl or NH(CR⁵⁵R⁵⁵)_(f)CH₃;

r is an integer 2 or 3;

f is an integer 0, 1 or 2;

wherein, V, Z, W, W′ are not all —H, and when Z is —R⁵², then at leastone of V, W, and W′ is not —H, alkyl, aralkyl, or heterocycloalkyl.

A further embodiment (“Embodiment 40”) is the compound of embodiment 21,wherein R⁵⁰ is selected from the group consisting

of —PO₃H₂, —P(O)[—OCR⁵² ₂OC(O)R⁵³]₂, —P(O)[—OCR⁵² ₂OC(O)OR⁵³]₂,—P(O)[—N(H)CR⁵² ₂C(O) OR⁵³]₂, —P(O)[—O-alk-SC(O)R⁵³]₂, —P(O)[—OCR⁵²₂OC(O)R⁵³][—R¹], —P(O)[—OCR⁵² ₂OC(O)OR⁵³][—R¹], —P(O)[—N(H)CR⁵²₂C(O)OR⁴³][—R¹], —P(O)[—OCH₂CH₂SC(O)R⁵³][—R¹], —P(O)(OH)(YR⁵¹),—P(O)(OR⁵⁶)(OR⁵⁶), —P(O)(OH)(—R¹), —P(O)[—OCR⁵² ₂OC(O)R⁵³](OR⁵⁶),—P(O)[—OCR⁵² ₂OC(O)OR⁵³](OR⁵⁶), —P(O)[—N(H)CR⁵² ₂ C(O)OR⁵³](OR⁵⁶),P(O)(OH)(NH₂), and —P(O)[—OCH(V)CH₂CH₂O—];

V is optionally substituted aryl or optionally substituted heteroaryl;

R⁵⁶ is —C₁-C₁₂ alkyl, —C₂-C₁₂ alkenyl, —C₂-C₁₂

alkynyl, —(CR⁷² ₂)_(n)aryl, —(CR⁵⁷ ₂)cycloalkyl, or —(CR⁵⁷₂)_(n)heterocycloalkyl, each optionally substituted;

each R⁵⁷ is independently selected from the group consisting ofhydrogen, optionally substituted —C₁-C₄ alkyl, halogen, optionallysubstituted —O—C₁-C₄ alkyl, —OCF₃, optionally substituted —S—C₁-C₄alkyl, —NR⁵⁸R⁵⁹, optionally substituted —C₂-C₄ alkenyl, and optionallysubstituted —C₂-C₄ alkynyl; with the proviso that when one R⁵⁷ isattached to C through an O, S, or N atom, then the other R⁵⁷ attached tothe same C is a hydrogen, or attached via a carbon atom;

R⁵⁸ is selected from hydrogen and optionally substituted —C₁-C₄ alkyl;and,

R⁵⁹ is selected from the group consisting of hydrogen and optionallysubstituted —C₁-C₄ alkyl, optionally substituted —C(O)—C₁-C₄ alkyl and—C(O)H.

A further embodiment (“Embodiment 41”) is the compound of embodiment 21,wherein R⁵⁰ is selected from the group consisting of

P(O)(OH)₂, —P(O)[—OCH₂OC(O)-t-butyl]₂, —P(O)[—OCH(CH₃)OC(O)-t-butyl]₂,—P(O)[—OCH(CH₃)OC(O)O-i-propyl]₂, —P(O)[—OCH₂OC(O)O-i-propyl]₂,—P(O)[—N(H)CH(CH₃)C(O)OCH₂ CH₃]₂, —P(O)[—N(H)C(CH₃)₂C(O)OCH₂CH₃]₂,—P(O)[—N(H)CH(CH₃)C(O)OCH₂CH₃][3,4-methylenedioxyphenyl],—P(O)[—N(H)C(CH₃)₂C(O)OCH₂CH₃][3,4-methylenedioxyphenyl],—P(O)[—O—CH₂CH₂S—C(O)CH₃]₂, —P(O)(OH)(OCH₃), —P(O)(OH)(OCH₂CH₃),—P(O)(OH)(CH₃), —P(O)[—OCH(3-chlorophenyl)CH₂CH₂O—],—P(O)[—OCH(pyrid-4-yl)CH₂CH₂O—], —P(O)[—OCH₂OC(O)-t-butyl](OCH₃),—P(O)[—OCH₂OC(O)O-i-propyl](OCH₃), —P(O)[—OCH(CH₃)OC(O)-t-butyl](OCH₃),—P(O)[—OCH(CH₃)OC(O)O-i-propyl](OCH₃), —P(O)[—N(H)CH(CH₃)C(O)OCH₂CH₃](OCH₃), —P(O)[—N(H)CH(CH₃)C(O)OCH₂CH₃](CH₃),—P(O)[—N(H)C(CH₃)₂C(O)OCH₂CH₃](OCH₃),—P(O)[—N(H)C(CH₃)₂C(O)OCH₂CH₃](CH₃), —P(O) [—OCH₂OC(O)-t-butyl](CH₃),—P(O)[—OCH₂OC(O)O-i-propyl](CH₃), —P(O)[—OCH(CH₃)OC(O)-t-butyl](CH₃),and —P(O)[—OCH(CH₃)OC(O)O-i-propyl](CH₃), and —P(O)[—OCH₂OC(O)O-ethyl]₂.

A further embodiment (“Embodiment 42”) is the compound of embodiment 21,wherein Y and Y¹ are each independently selected from —O— and —NR⁶⁰—;and together R⁵¹ and R⁵¹ are the group

wherein, V is substituted aryl or substituted heteroaryl.

A further embodiment (“Embodiment 43”) is the compound of embodiment 21,wherein G² is CR⁴ or N, or together G² and X are connected to form acyclic group containing 5-7 atoms, wherein 0-2 atoms of said cyclicgroup are heteroatoms and the remaining atoms of said cyclic group arecarbon atoms substituted with alkyl, aryl, cycloalkyl or heteroaryl.

A further embodiment (“Embodiment 44”) is the compound of embodiment 43,wherein G² is CR⁴.

A further embodiment (“Embodiment 45”) is the compound of embodiment 44,wherein R⁴ is H.

A further embodiment (“Embodiment 46”) is the compound of embodiment 43,wherein together G² and X are connected to form a cyclic groupcontaining 5-7 atoms, wherein 0-2 atoms of said cyclic group areheteroatoms and the remaining atoms of said cyclic group are carbonatoms substituted with alkyl, aryl, cycloalkyl or heteroaryl.

A further embodiment (“Embodiment 47”) is the compound of embodiment 43,wherein G² is N.

A further embodiment (“Embodiment 48”) is the compound of embodiment 21,wherein:

X is selected from the group consisting of alkyloxy and cycloalkyloxy;

R² is selected from the group consisting of phenylene-O—,methylene-phenylene-O—, phenylene-methylene-O—, furan-2-yl-5-methylene,thiophen-2-yl-5-methylene, pyridin-diyl-O—, pyrimidin-diyl-O—,pyridazin-diyl-O— and pyrazin-diyl-O—, each optionally substituted withone or two groups independently selected from halogen, CN, CF₃, NR⁵ ₂,—C₁₋₄-alkyl, —S(O)₂R⁵ or —OR⁵, wherein R² is connected to R⁵⁰ by a Cring atom;

G¹, G² and G³ are CR⁴ and R⁴ is H;

D is selected from the group consisting of thiazolyl,1,3,4-thiadiazolyl, 1,2,4-thiadiazolyl, each optionally substituted withone or two groups selected from halogen, CF₃, or optionally substitutedC₁₋₄-alkyl; and

R⁵⁰ is selected from the group consisting of:

P(O)(OH)₂, —P(O)[—OCH₂OC(O)-t-butyl]₂, —P(O)[—OCH(CH₃)OC(O)-t-butyl]₂,—P(O)[—OCH(CH₃)OC(O)O-i-propyl]₂, —P(O)[—OCH₂OC(O)O-i-propyl]₂,—P(O)[—OCH₂OC(O)O-ethyl]₂, —P(O)[—N(H)CH(CH₃)C(O)OCH₂CH₃]₂,—P(O)[—N(H)C(CH₃)₂C(O)OCH₂CH₃]₂, —P(O)[—OCH(3-chlorophenyl)CH₂CH₂O—],—P(O)[—OCH(pyrid-4-yl)CH₂CH₂O—], or —P(O)[—OCH(V)CH₂CH₂O—];

and V is optionally substituted aryl or optionally substitutedheteroaryl.

A further embodiment (“Embodiment 49”) is the compound of embodiment 44,wherein R² is phenylene-O—.

A further embodiment (“Embodiment 50”) is the compound of embodiment 21,wherein:

X is selected from the group consisting of alkyloxy and cycloalkyloxy;

R² is optionally substituted methylene-thiophen-2,5-diyl, phenylene-O—or thiophen-2-yl-5-methylene, wherein R⁵⁰ is attached to phenylene orthiophenyl;

G¹, G² and G³ are CH;

D is thiazolyl, optionally substituted with one or two groups selectedfrom halogen, CF₃, or optionally substituted C₁₋₄-alkyl;

R⁵⁰ is selected from the group consisting of —P(O)(OH)₂,—P(O)[—OCH₂OC(O)-t-butyl]₂, —P(O)[—OCH(CH₃)OC(O)-t-butyl]₂,—P(O)[—OCH(CH₃)OC(O)O-i-propyl]₂, —P(O)[—OCH₂OC(O)O-i-propyl]₂,—P(O)[—OCH₂OC(O)O-ethyl]₂, —P(O)[—N(H)CH(CH₃)C(O)OCH₂CH₃]₂,—P(O)[—N(H)C(CH₃)₂C(O)OCH₂CH₃]₂, —P(O)[—OCH(3-chlorophenyl)CH₂CH₂O—],—P(O)[—OCH(pyrid-4-yl)CH₂CH₂O—], or —P(O)[—OCH(V)CH₂CH₂O—];

and V is optionally substituted aryl or optionally substitutedheteroaryl.

A further embodiment (“Embodiment 51”) is the compound of embodiment 21,wherein said compound has one of the following combinations ofsubstituents:

Substituent Combination Nos. #1 1, 2 #2 1, 3 #3 1, 4 #4 1, 5 #5 1, 6 #62, 3 #7 2, 4 #8 2, 5 #9 2, 6 #10 3, 4 #11 3, 5 #12 3, 6 #13 4, 5 #14 4,6 #15 5, 6 #16 1, 2, 3 #17 1, 2, 4 #18 1, 2, 5 #19 1, 2, 6 #20 1, 3, 4#21 1, 3, 5 #22 1, 3, 6 #23 1, 4, 5 #24 1, 4, 6 #25 1, 5, 6 #26 2, 3, 4#27 2, 3, 5 #28 2, 3, 6 #29 2, 4, 5 #30 2, 4, 6 #31 2, 5, 6 #32 3, 4, 5#33 3, 4, 6 #34 3, 5, 6 #35 4, 5, 6 #36 1, 2, 3, 4 #37 1, 2, 3, 5 #38 1,2, 3, 6 #39 1, 2, 4, 5 #40 1, 2, 4, 6 #41 1, 2, 5, 6 #42 1, 3, 4, 5 #431, 3, 4, 6 #44 1, 3, 5, 6 #45 1, 4, 5, 6 #46 2, 3, 4, 5 #47 2, 3, 4, 6#48 2, 3, 5, 6 #49 2, 4, 5, 6 #50 3, 4, 5, 6 #51 1, 2, 3, 4, 5 #52 1, 2,3, 4, 6 #53 1, 2, 3, 5, 6 #54 1, 2, 4, 5, 6 #55 1, 3, 4, 5, 6 #56 2, 3,4, 5, 6 #57 1, 2, 3, 4, 5, 6wherein:

substituent not listed in said combination is as defined in embodiment21;

G² is CR⁴ or N and R⁴ is H, halogen or optionally substituted alkyl, or

together G² and X are connected to form a cyclic group containing 5-7atoms, wherein 0-2 atoms of said cyclic group are heteroatoms and theremaining atoms of said cyclic group are carbon atoms substituted withalkyl, aryl, cycloalkyl or heteroaryl;

Substituent 1 is X and:

X is selected from the group consisting of aryl, heteroaryl, alkyl,cycloalkyl, arylalkyl, aryloxy, heteroaryloxy, alkyloxy, cycloalkyloxyand arylalkyloxy; or

X is selected from the group consisting of alkyl, cycloalkyl, alkyloxy,cycloalkyloxy and aryloxy; or

X is selected from the group consisting of alkyloxy and cycloalkyloxy;Substituent 2 is R² and:

R² is optionally substituted and is selected from arylene,heteroarylene, alkylene, cycloalkylene, arylalkylene, alkylarylene,arylene-O—, heteroarylene-O—, alkylene-O—, cycloalkylene-O—,arylalkylene-O—, alkylarylene-O—, arylene-S—, heteroarylene-S—,alkylene-S—, cycloalkylene-S—, arylalkylene-S—, or alkylarylene-S—,wherein R² is connected to R⁵⁰ by a C atom; or

R² is -E¹-E²-E³-E¹-E, wherein E⁴ is connected to R⁵⁰

E¹ is a bond, O or S;

E² is a bond or alkylene;

E³ is optionally substituted C₁₋₄-alkylene, optionally substitutedC₃₋₈-cycloalkylalkylene, arylene or heteroarylene optionally substitutedwith one or two groups independently selected from aryl, heteroaryl,cycloalkyl, cycloalkenyl, halogen, CN, CF₃, NR⁵ ₂, —C₁₋₄-alkyl, —S(O)₂R⁵or —OR⁵; wherein, when both E¹ and E² are a bond, together they form asingle bond;

R⁵ is optionally substituted alkyl or cycloalkyl; and

E⁴ is a bond or alkylene; or

R² is selected from the group consisting of phenylene-O—,methylene-phenylene-O—, phenylene-methylene-O—, furan-2-yl-5-methylene,thiophen-2-yl-5-methylene, pyridin-diyl-O—, pyrimidin-diyl-O—,pyridazin-diyl-O— and pyrazin-diyl-O—, each optionally substituted withone or two groups independently selected from aryl, heteroaryl, halogen,CN, CF₃, NR⁵ ₂, —C₁₋₄-alkyl, —S(O)₂R⁵ or —OR⁵, wherein R⁵⁰ is connectedto R² by a carbon atom; or R² is methylene-thiophen-2,5-diyl,phenylene-O— or thiophen-2-yl-5-methylene, wherein R⁵⁰ is connected tothe phenylene or thiophenyl group;

Substituent 3 is G¹ and:

G¹ is N; or

G¹ is CR⁴ and R⁴ is H, halogen or optionally substituted alkyl;

Substituent 4 is G³ and:

G³ is N; or

G³ is CR⁴ and R⁴ is H, halogen or optionally substituted alkyl;

Substituent 5 is D and:

D is selected from a group consisting of heteroaryl or aryl; or

D is a heteroaryl having a nitrogen as a ring atom, said heteroarylcomprising a nitrogen ring atom adjacent to a carbon ring atom, whereinsaid carbon ring atom is connected to the amide nitrogen atom adjacentto D, and wherein said heteroaryl has an additional 0 to 3 heteroatomsindependently selected from O, S or N; or

D is selected from the group consisting of pyridinyl, thiazolyl,1,3,4-thiadiazolyl, 1,2,4-thiadiazolyl, oxazolyl, isoxazolyl,imidazolyl, pyrazolyl, pyrazinyl, pyridazinyl, pyrimidinyl,benzothiazolyl and 5,6-dihydro-4H-cyclopentathiazolyl, each optionallysubstituted with one or two groups selected from halogen, CF₃, oroptionally substituted C₁₋₄-alkyl; or

D is selected from the group consisting of thiazolyl,1,3,4-thiadiazolyl, 1,2,4-thiadiazolyl, each optionally substituted withone or two groups selected from halogen, CF₃, or optionally substitutedC₁₋₄-alkyl; and

Substituent 6 is R⁵¹ and:

R⁵⁰ is —P(O)(Y²R⁵¹) R¹ or —P(O)(YR⁵¹)Y¹R⁵¹;

R¹ is selected from the group consisting of hydrogen, optionallysubstituted —C₁-C₆-alkyl, —CF₃, —CHF₂, —CH₂F, —CH₂OH, optionallysubstituted —C₂-C₆ alkenyl, optionally substituted —C₂-C₆ alkynyl,optionally substituted —(CR⁵² ₂)cycloalkyl, optionally substituted (CR⁵²₂)_(n)heterocycloalkyl, —(CR⁵² ₂)_(k) S(═O)R⁵³, —(CR⁵² ₂)_(k) S(═O)₂R⁵³;

Y, Y¹ and Y² are each independently selected from —O— or —NR⁶⁰—;

wherein,

when Y² is —O— or when Y and Y¹ are both —O—, R⁵¹ attached to —O— isindependently selected from —H, alkyl, optionally substituted aryl,optionally substituted heterocycloalkyl, optionally substituted—CH₂-heterocycloakyl wherein the cyclic moiety contains a carbonate orthiocarbonate, optionally

substituted -alkylaryl, —C(R⁵²)₂OC(O)NR⁵² ₂, —NR⁵²—C(O)—R⁵³, —C(R⁵²₂)₂—OC(O)R⁵³, —C(R⁵²)₂—O— C)OR⁵³, —C(R⁵²)₂OC(O)SR⁵³, -alkyl-S—C(O)R⁵³,-alkyl-S—S-alkylhydroxy.and -alkyl-S—S—S-alkylhydroxy; or

when Y² is —NR⁶⁰— or when Y and Y¹ are both —NR⁶⁰—, then R⁵¹ attached to—NR⁶⁰— is independently selected from —H, —[C(R⁵²)₂]_(r)—COOR⁵³,—C(R⁵⁴)₂COOR⁵³, —[C(R⁵²)₂]_(r)—C(O)SR⁵³, and -cycloalkylene-COOR⁵³; or

when Y is —O— and Y¹ is NR⁶⁰, then R⁶¹ attached to —O— is independentlyselected from —H, alkyl, optionally substituted aryl, optionallysubstituted heterocycloalkyl, optionally substituted CH₂-heterocycloakylwherein the cyclic moiety contains a carbonate or thiocarbonate,optionally substituted -alkylaryl, —C(R⁵²)₂OC(O)NR⁵² ₂, —NR⁵²—C(O)—R⁵³,—C(R⁵²)₂—OC(O)R⁵³, —C(R⁵²)₂—O—C(O)OR⁵³, —C(R⁵²)₂OC(O)SR⁵³,-alkyl-S—C(O)R⁵³, -alkyl-S—S-alkylhydroxy, and-alkyl-S—S—S-alkylhydroxy, and R⁵¹ attached to —NR⁶⁰— is independentlyselected from —H, —[C(R⁵²)₂]_(r)—COOR⁵³, —C(R⁵⁴)₂COOR⁵³,—[C(R⁵²)₂]_(r)—C(O)SR⁵³, and -cycloalkylene-COOR⁵³, wherein if both R⁵¹are alkyl, at least one is higher alkyl; or

when Y and Y¹ are independently selected from —O— and —NR⁶⁰—, then R⁵¹and R⁵¹ together form a cyclic group comprising -alkyl-S—S-alkyl-, orR⁵¹ and R⁵¹ together are the group

wherein,

V, W, and W′ are independently selected from the group consisting ofhydrogen, optionally substituted alkyl, optionally substituted aralkyl,heterocycloalkyl, aryl, substituted aryl, heteroaryl, substitutedheteroaryl, optionally substituted 1-alkenyl, and optionally substituted1-alkynyl, and

Z is —CHR⁵²OH, —CHR⁵²OC(O)R⁵³, —CHR⁵²OC(S)R⁵³, —CHR⁵²OC(S)OR⁵³,—CHR⁵²OC(O)SR⁵³, —CHR⁵²OCO₂R⁵³, —OR⁵², —SR⁵², —CHR⁵²N₃, —CH₂aryl,—CH(aryl)OH, —CH(CH═CR⁵² ₂)OH, —CH(C≡CR⁵²)OH, —R⁵², —NR⁵² ₂, —O COR⁵³,—OCO₂R⁵³, —SCOR⁵³, —SCO₂R⁵³, —NHCOR⁵², —NHCO₂R⁵³, —CH₂NHaryl,—(CH₂)_(r)—OR⁵² or —(CH₂)_(r)—SR⁵¹; or

W and W are as defined above and together V and Z are connected via anadditional 3-5 atoms to form a cyclic group containing 5-7 atoms,wherein 0-1 atoms are heteroatoms and the remaining atoms are carbon; or

W′ and Z are as defined above and together V and W are connected via anadditional 3 carbon atoms to form an optionally substituted cyclic groupcontaining 6 carbon atoms or carbon substituted by hydrogen andsubstituted with one substituent selected from hydroxy, acyloxy,alkoxycarbonyloxy, alkylthiocarbonyloxy or aryloxycarbonyloxy which isattached to one of said carbon atoms that is three atoms from a Yattached to the phosphorus; or

V and W′ are as defined above and together Z and W are connected via anadditional 3-5 atoms to form a cyclic group, wherein 0-1 atoms areheteroatoms and the remaining atoms are carbon or carbon substituted byhydrogen, and V must be aryl, substituted aryl, heteroaryl, orsubstituted heteroaryl; or

V and Z are as defined above and together W and W′ are connected via anadditional 2-5 atoms to form a cyclic group, wherein 0-2 atoms areheteroatoms and the remaining atoms are carbon, where V must be aryl,substituted aryl, heteroaryl, or substituted heteroaryl;

R⁵² is R⁵³ or —H;

R⁵³ is alkyl, aryl, heterocycloalkyl or aralkyl;

R⁵⁴ is independently selected from —H or alkyl, or together R⁵⁴ and R⁵⁴form a cycloalkylene group;

R⁶⁰ is —H, lower alkyl, acyloxyalkyl, alkoxycarbonyloxyalkyl, loweracyl, C₁₋₆-perfluoroalkyl or NH(CR⁵⁵R⁵⁵)CH₃;

r is an integer 2 or 3;

f is an integer 0, 1 or 2;

-   -   wherein, V, Z, W, W′ are not all —H, and when Z is —R⁵², then at        least one of V, W, and W′ is not —H, alkyl, aralkyl, or        heterocycloalkyl; or

R⁵⁰ is selected from the group consisting

of —PO₃H₂, —P(O)[—OCR⁵² ₂OC(O)R⁵³]₂, —P(O)[—OCR⁵² ₂OC(O)OR⁵³]₂,—P(O)[—N(H)CR⁵² ₂C(O) OR⁵³]₂, —P(O)[—O-alk-SC(O)R⁵³]₂, —P(O)[—OCR⁵²₂OC(O)R⁵³][—R¹], —P(O)[—OCR⁵² ₂OC(O)OR⁵³][—R¹], —P(O)[—N(H)CR⁵²₂C(O)OR⁵³][—R¹], —P(O)[—OCH₂CH₂SC(O)R⁵³][—R¹], —P(O)(OH)(YR⁵¹),—P(O)(OR⁵⁶)(OR⁵⁶), —P(O)(OH)(—R¹), —P(O)[—OCR⁵² ₂OC(O)R⁵³](OR⁵⁶),—P(O)[—OCR⁵² ₂OC(O)OR⁵³](OR⁵⁶), —P(O)[—N(H)CR⁵² ₂ C(O)OR⁵³](OR⁵⁶),P(O)(OH)(NH₂), and —P(O)[—OCH(V)CH₂CH₂O—];

V is optionally substituted aryl or optionally substituted heteroaryl;

R⁵⁶ is —C₁-C₁₂ alkyl, —C₂-C₁₂ alkenyl, —C₂-C₁₂

alkynyl, —(CR⁵⁷ ₂)_(n)aryl, —(CR⁵⁷ ₂)_(n)cycloalkyl, or —(CR⁵²₂)_(n)heterocycloalkyl, each optionally substituted;

each R⁵⁷ is independently selected from the group consisting ofhydrogen, optionally substituted —C₁-C₄ alkyl, halogen, optionallysubstituted —O—C₁-C₄ alkyl, —OCF₃, optionally substituted —S—C₁-C₄alkyl, —NR⁵⁸R⁵⁹, optionally substituted —C₂-C₄ alkenyl, and optionallysubstituted —C₂-C₄ alkynyl; with the proviso that when one R⁵⁷ isattached to C through an O, S, or N atom, then the other R⁵⁷ attached tothe same C is a hydrogen, or attached via a carbon atom;

R⁵¹ is selected from hydrogen and optionally substituted —C₁-C₄ alkyl;and,

R⁵⁹ is selected from the group consisting of hydrogen and optionallysubstituted —C₁-C₄ alkyl, optionally substituted —C(O)—C₁-C₄ alkyl and—C(O)H; or

R⁵⁰ is —P(O)(OH)₂, —P(O)[—OCH₂OC(O)-r-butyl]₂,—P(O)[—OCH(CH₃)OC(O)-t-butyl]₂, —P(O)[—OCH(CH₃)OC(O)O-i-propyl]₂,—P(O)[—OCH₂OC(O)O-i-propyl]₂, —P(O)[—OCH₂OC(O)O-ethyl]₂,—P(O)[—N(H)CH(CH₃)C(O)OCH₂CH₃]₂, —P(O) [—N(H)C(CH₃)₂C(O)OCH₂CH₃]₂,—P(O)[—OCH(3-chlorophenyl)CH₂CH₂O—], —P(O)[—OCH(pyrid-4-yl)CH₂CH₂O—], or—P(O)[—OCH(V)CH₂CH₂O—]; and V is optionally substituted aryl oroptionally substituted heteroaryl; or

R⁵⁰ is selected from the group consisting of —P(O)(OH)₂,—P(O)[—OCH₂OC(O)-t-butyl]₂, —P(O)[—OCH(CH₃)OC(O)-t-butyl]₂,—P(O)[—OCH(CH₃)OC(O)O-i-propyl]₂, —P(O)[—OCH₂OC(O)O-i-propyl]₂,—P(O)[—N(H)CH(CH₃)C(O)OCH₂ CH₃]₂, —P(O)[—N(H)C(CH₃)₂C(O)OCH₂CH₃]₂,—P(O)[—N(H)CH(CH₃)C(O)OCH₂CH₃][3,4-methylenedioxyphenyl],—P(O)[—N(H)C(CH₃)₂C(O)OCH₂CH₃][3,4-methylenedioxyphenyl],—P(O)[—O—CH₂CH₂S—C(O)CH₃]₂, —P(O)(OH)(OCH₃), —P(O)(OH)(OCH₂CH₃),—P(O)(OH)(CH₃), —P(O)[—OCH(3-chlorophenyl)CH₂CH₂O—],—P(O)[—OCH(pyrid-4-yl)CH₂CH₂O—], —P(O)[—OCH₂OC(O)-t-butyl](OCH₃),—P(O)[—OCH₂OC(O)O-i-propyl](OCH₃), —P(O)[—OCH(CH₃)OC(O)-t-butyl](OCH₃),—P(O)[—OCH(CH₃)OC(O)O-i-propyl](OCH₃), —P(O)[—N(H)CH(CH₃)C(O)OCH₂CH₃](OCH₃), —P(O)[—N(H)CH(CH₃)C(O)OCH₂CH₃](CH₃),—P(O)[—N(H)C(CH₃)₂C(O)OCH₂CH₃](OCH₃),—P(O)[—N(H)C(CH₃)₂C(O)OCH₂CH₃](CH₃), —P(O) [—OCH₂OC(O)-t-butyl](CH₃),—P(O)[—OCH₂OC(O)O-i-propyl](CH₃), —P(O)[—OCH(CH₃)OC(O)-t-butyl](CH₃),—P(O)[—OCH(CH₃)OC(O)O-i-propyl](CH₃),

and —P(O)[—OCH₂OC(O)O-ethyl]₂.

A further embodiment (“Embodiment 52”) is the compound of embodiment 51,wherein:

Substituent 1 is X and:

X is selected from the group consisting of aryl, heteroaryl, alkyl,cycloalkyl, arylalkyl, aryloxy, heteroaryloxy, alkyloxy, cycloalkyloxyand arylalkyloxy;

Substituent 2 is R² and:

R² is optionally substituted and is selected from arylene,heteroarylene, alkylene, cycloalkylene, arylalkylene, alkylarylene,arylene-O—, heteroarylene-O—, alkylene-O—, cycloalkylene-O—,arylalkylene-O—, alkylarylene-O—, arylene-S—, heteroarylene-S—,alkylene-S—, cycloalkylene-S—, arylalkylene-S—, alkylarylene-S—, whereinR⁵⁰ is connected to R² by a carbon atom;

Substituent 3 is G¹ and:

G¹ is N; or

G¹ is CR⁴ and R⁴ is H, halogen or optionally substituted alkyl;

Substituent 4 is G³ and:

G³ is N; or

G³ is CR¹ and R⁴ is H, halogen or optionally substituted alkyl;

Substituent 5 is D and:

D is selected from a group consisting of heteroaryl or aryl; or

and

Substituent 6 is R⁵⁰ and:

R⁵⁰ is —P(O)(Y²R⁵¹) R¹ or —P(O)(YR⁵¹)Y¹R⁵¹;

R¹ is selected from the group consisting of hydrogen, optionallysubstituted —C₁-C₆-alkyl, —CF₃, —CHF₂, —CH₂F, —CH₂OH, optionallysubstituted —C₂-C₆ alkenyl, optionally substituted —C₂-C₆ alkynyl,optionally substituted —(CR⁵² ₂)cycloalkyl, optionally substituted (CR⁵²₂)_(n)heterocycloalkyl, —(CR⁵² ₂)_(k) S(═O)R⁵³, —(CR⁵² ₂)_(k)S(═O)₂R⁵³;

Y, Y¹ and Y² are each independently selected from —O— or —NR⁶⁰—;

wherein,

when Y² is —O— or when Y and Y¹ are both —O—, R⁵¹ attached to —O— isindependently selected from —H, alkyl, optionally substituted aryl,optionally substituted heterocycloalkyl, optionally substituted—CH₂-heterocycloakyl wherein the cyclic moiety contains a carbonate orthiocarbonate, optionally

substituted -alkylaryl, —C(R⁵²)₂OC(O)NR⁵² ₂, —NR⁵²—C(O)—R⁵³,—C(R⁵²)₂—OC(O)R⁵³, —C(R⁵²)₂—O—C(O)OR⁵³, —C(R⁵²)₂OC(O)SR⁵³,-alkyl-S—C(O)R⁵³, -alkyl-S—S-alkylhydroxy,and -alkyl-S—S—S-alkylhydroxy; or

when Y² is —NR⁶⁰— or when Y and Y¹ are both —NR⁶⁰—, then R⁵¹ attached to—NR⁶⁰— is independently selected from —H, —[C(R⁵²)₂]_(r)—COOR⁵³,—C(R⁵⁴)₂)COOR⁵³, —[C(R⁵²)₂]_(r)—C(O)SR⁵³, and -cycloalkylene-COOR⁵³; or

when Y is —O— and Y¹ is NR⁶⁰, then R⁵¹ attached to —O— is independentlyselected from —H, alkyl, optionally substituted aryl, optionallysubstituted heterocycloalkyl, optionally substituted CH₂-heterocycloakylwherein the cyclic moiety contains a carbonate or thiocarbonate,optionally substituted -alkylaryl, —C(R⁵²)₂OC(O)NR⁵² ₂, —NR⁵²—C(O)—R⁵³,—C(R⁵²)₂—OC(O)R⁵³, —C(R⁵²)₂—O—C(O)OR⁵³, —C(R⁵²)₂OC(O)SR⁵³,-alkyl-S—C(O)R⁵³, -alkyl-S—S-alkylhydroxy, and-alkyl-S—S—S-alkylhydroxy, and R⁵¹ attached to —NR⁶⁰— is independentlyselected from —H, —[C(R⁵²)₂]_(r)—COOR⁵³, —C(R⁵⁴)₂COOR⁵³,—[C(R⁵²)₂]_(r)—C(O)SR⁵³, and -cycloalkylene-COOR⁵³, wherein if both R⁵¹are alkyl, at least one is higher alkyl; or

when Y and Y¹ are independently selected from —O— and —NR⁶⁰—, then R⁵¹and R⁵¹ together form a cyclic group comprising -alkyl-S—S-alkyl-, orR⁵¹ and R⁵¹ together are the group

wherein,

V, W, and W′ are independently selected from the group consisting ofhydrogen, optionally substituted alkyl, optionally substituted aralkyl,heterocycloalkyl, aryl, substituted aryl, heteroaryl, substitutedheteroaryl, optionally substituted 1-alkenyl, and optionally substituted-alkynyl, and

Z is —CHR⁵²OH, —CHR⁵²OC(O)R⁵³, —CHR⁵²OC(S)R⁵³, —CHR⁵²OC(S)OR⁵³,—CHR⁵²OC(O)SR⁵³, —CHR⁵²OCO₂R⁵³, —OR⁵², —SR⁵², —CHR⁵²N₃, —CH₂aryl,—CH(aryl)OH, —CH(CH═CR⁵² ₂)OH, —CH(C≡CR⁵²)OH, —R⁵², —NR⁵² ₂, —O COR⁵³,—OCO₂R⁵³, —SCOR⁵³, —SCO₂R⁵³, —NHCOR⁵², —NHCO₂R⁵³, —CH₂NHaryl,—(CH₂)_(r)—OR⁵² or —(CH₂)_(r)—SR⁵²; or

W and W are as defined above and together V and Z are connected via anadditional 3-5 atoms to form a cyclic group containing 5-7 atoms,wherein 0-1 atoms are heteroatoms and the remaining atoms are carbon; or

W′ and Z are as defined above and together V and W are connected via anadditional 3 carbon atoms to form an optionally substituted cyclic groupcontaining 6 carbon atoms or carbon substituted by hydrogen andsubstituted with one substituent selected from hydroxy, acyloxy,alkoxycarbonyloxy, alkylthiocarbonyloxy or aryloxycarbonyloxy which isattached to one of said carbon atoms that is three atoms from a Yattached to the phosphorus; or

V and W′ are as defined above and together Z and W are connected via anadditional 3-5 atoms to form a cyclic group, wherein 0-1 atoms areheteroatoms and the remaining atoms are carbon or carbon substituted byhydrogen, and V must be aryl, substituted aryl, heteroaryl, orsubstituted heteroaryl; or

V and Z are as defined above and together W and W′ are connected via anadditional 2-5 atoms to form a cyclic group, wherein 0-2 atoms areheteroatoms and the remaining atoms are carbon, where V must be aryl,substituted aryl, heteroaryl, or substituted heteroaryl;

R⁵² is R⁵³ or —H;

R⁵³ is alkyl, aryl, heterocycloalkyl or aralkyl;

R⁵⁴ is independently selected from —H or alkyl, or together R⁵⁴ and R⁵⁴form a cycloalkylene group;

R⁶⁰ is —H, lower alkyl, acyloxyalkyl, alkoxycarbonyloxyalkyl, loweracyl, C₁₋₆-perfluoroalkyl or NH(CR⁵⁵R⁵⁵)_(f)CH₃;

r is an integer 2 or 3;

f is an integer 0, 1 or 2;

wherein, V, Z, W, W′ are not all —H, and when Z is —R⁵², then at leastone of V, W, and W′ is not —H, alkyl, aralkyl, or heterocycloalkyl.

A further embodiment (“Embodiment 53”) is the compound of embodiment 51,wherein:

Substituent 1 is X and:

X is selected from the group consisting of alkyl, cycloalkyl, alkyloxy,cycloalkyloxy and aryloxy;

Substituent 2 is R² and:

R² is -E¹-E²-E³-E⁴-, wherein E⁴ is connected to R⁵⁰;

E¹ is a bond, O or S;

E² is a bond or alkylene;

E³ is optionally substituted C₁₋₄-alkylene, optionally substitutedC₃₋₈-cycloalkylalkylene, arylene or heteroarylene optionally substitutedwith one or two groups independently selected from aryl, heteroaryl,cycloalkyl, cycloalkenyl, halogen, CN, CF₃, NR⁵ ₂, —C₁₋₄-alkyl, —S(O)₂R⁵or —OR⁵; wherein, when both E¹ and E² are a bond, together they form asingle bond,

R⁵ is optionally substituted alkyl or cycloalkyl; and

E⁴ is a bond or alkylene:

Substituent 3 is G¹ and:

G¹ is N; or

G¹ is CR⁴ and R⁴ is H, halogen or optionally substituted alkyl;

Substituent 4 is G¹ and:

G³ is N; or

G³ is CR⁴ and R⁴ is H, halogen or optionally substituted alkyl;

Substituent 5 is D and:

D is a heteroaryl having a nitrogen as a ring atom, said heteroarylcomprising a nitrogen ring atom adjacent to a carbon ring atom, whereinsaid carbon ring atom is connected to the amide nitrogen atom adjacentto D, and wherein said heteroaryl has an additional 0 to 3 heteroatomsindependently selected from O, S or N; and

Substituent 6 is R⁵⁰ and:

R⁵⁰ is selected from the group consisting

of —PO₃H₂, —P(O)[—OCR⁵² ₂OC(O)R⁵³]₂, —P(O)[—OCR⁵² ₂OC(O)OR⁵³]₂,—P(O)[—N(H)CR⁵² ₂C(O) OR⁵³]₂, —P(O)[—O-alk-SC(O)R⁵³]₂, —P(O)[—OCR⁵²₂OC(O)R⁵³][—R¹], —P(O)[—OCR⁵² ₂OC(O)OR⁵³][—R¹], —P(O)[—N(H)CR⁵²₂C(O)OR⁵³][—R¹], —P(O)[—OCH₂CH₂SC(O)R⁵³][—R¹], —P(O)(OH)(YR⁵¹),—P(O)(OR⁵⁶)(OR⁵⁶), —P(O)(OH)(—R¹), —P(O)[—OCR⁵² ₂OC(O)R⁵³](OR⁵⁶),—P(O)[—OCR⁵² ₂OC(O)OR⁵³](OR⁵⁶), —P(O)[—N(H)CR⁵² ₂ C(O)OR⁵³](OR⁵⁶),P(O)(OH)(NH₂), and —P(O)[—OCH(V)CH₂CH₂O—];

V is optionally substituted aryl or optionally substituted heteroaryl;

R⁵⁶ is —C₁-C₁₂ alkyl, —C₂-C₁₂ alkenyl, —C₂-C₁₂

alkynyl, —(CR⁵⁷ ₂)_(n)aryl, —(CR⁵⁷ ₂)_(n)cycloalkyl, or —(CR⁵⁷₂)_(n)heterocycloalkyl, each optionally substituted;

each R⁵⁷ is independently selected from the group consisting ofhydrogen, optionally substituted —C₁-C₄ alkyl, halogen, optionallysubstituted —O—C₁-C₄ alkyl, —OCF₃, optionally substituted —S—C₁-C₄alkyl, —NR⁵⁸R⁵⁹, optionally substituted —C₂-C₄ alkenyl, and optionallysubstituted —C₂-C₄ alkynyl; with the proviso that when one R⁵⁷ isattached to C through an O, S, or N atom, then the other R⁵⁷ attached tothe same C is a hydrogen, or attached via a carbon atom;

R⁵⁸ is selected from hydrogen and optionally substituted —C₁-C₄ alkyl;and,

R⁵⁹ is selected from the group consisting of hydrogen and optionallysubstituted —C₁-C₄ alkyl, optionally substituted —C(O)—C₁-C₄ alkyl and—C(O)H.

A further embodiment (“Embodiment 54”) is the compound of embodiments51, 52 or 53, wherein G¹, G² and G³ are CR⁴ and R⁴ is H, halogen oroptionally substituted alkyl.

A further embodiment (“Embodiment 55”) is the compound of embodiment 54,wherein R⁴ is H.

A further embodiment (“Embodiment 56”) is the compound of embodiments51, 52, 53, 54 or 55, wherein R⁵⁰ is —P(O)(OH)₂,—P(O)[—OCH₂OC(O)-t-butyl]₂, —P(O)[—OCH(CH₃)OC(O)-t-butyl]₂,—P(O)[—OCH(CH₃)OC(O)O-i-propyl]₂, —P(O)[—OCH₂OC(O)O-i-propyl]₂,—P(O)[—OCH₂OC(O)O-ethyl]₂, —P(O)[—N(H)CH(CH₃)C(O)OCH₂CH₃]₂,—P(O)[—N(H)C(CH₃)₂C(O)OCH₂CH₃]₂, —P(O)[—OCH(3-chlorophenyl)CH₂CH₂O—],—P(O)[—OCH(pyrid-4-yl)CH₂CH₂O—], or —P(O)[—OCH(V)CH₂CH₂O—]; and V isoptionally substituted aryl or optionally substituted heteroaryl.

A further embodiment (“Embodiment 57”) is the compound of embodiments51, 52, 53, 54, 55 or 56, wherein

R⁵⁰ is selected from the group consisting of —P(O)(OH)₂,—P(O)[—OCH₂OC(O)-t-butyl]₂, —P(O)[—OCH(CH₃)OC(O)-t-butyl]₂,—P(O)[—OCH(CH₃)OC(O)O-i-propyl]₂, —P(O)[—OCH₂OC(O)O-i-propyl]₂,—P(O)[—N(H)CH(CH₃)C(O)OCH₂ CH₃]₂, —P(O)[—N(H)C(CH₃)₂C(O)OCH₂CH₃]₂,—P(O)[—N(H)CH(CH₃)C(O)OCH₂CH₃][3,4-methylenedioxyphenyl],—P(O)[—N(H)C(CH₃)₂C(O)OCH₂CH₃][3,4-methylenedioxyphenyl],—P(O)[—O—CH₂CH₂S—C(O)CH₃]₂, —P(O)(OH)(OCH₃), —P(O)(OH)(OCH₂CH₃),—P(O)(OH)(CH₃), —P(O)[—OCH(3-chlorophenyl)CH₂CH₂O—],—P(O)[—OCH(pyrid-4-yl)CH₂CH₂O—], —P(O)[—OCH₂OC(O)-t-butyl](OCH₃),—P(O)[—OCH₂OC(O)O-i-propyl](OCH₃), —P(O)[—OCH(CH₃)OC(O)-t-butyl](OCH₃),—P(O)[—OCH(CH₃)OC(O)O-i-propyl](OCH₃), —P(O)[—N(H)CH(CH₃)C(O)OCH₂CH₃](OCH₃), —P(O)[—N(H)CH(CH₃)C(O)OCH₂CH₃](CH₃),—P(O)[—N(H)C(CH₃)₂C(O)OCH₂CH₃](OCH₃),—P(O)[—N(H)C(CH)₂C(O)OCH₂CH₃](CH₃), —P(O) [—OCH₂OC(O)-t-butyl](CH₃),—P(O)[—OCH₂OC(O)O-i-propyl](CH₃), —P(O)[—OCH(CH₃)OC(O)-t-butyl](CH₃),—P(O)[—OCH(CH₃)OC(O)O-i-propyl](CH₃),

and —P(O)[—OCH₂OC(O)O-ethyl]₂.

A further embodiment (“Embodiment 58”) is the compound of embodiments51, 52, 53, 54, 55, 56 or 57, wherein X is selected from the groupconsisting of alkyloxy and cycloalkyloxy.

A further embodiment (“Embodiment 59”) is the compound of embodiments51, 52, 53, 54, 55, 56, 57 or 58, wherein R² is selected from the groupconsisting of phenylene-O—, methylene-phenylene-O—,phenylene-methylene-O—, furan-2-yl-5-methylene,thiophen-2-yl-5-methylene, pyridin-diyl-O—, pyrimidin-diyl-O—,pyridazin-diyl-O— and pyrazin-diyl-O—, each optionally substituted withone or two groups independently selected from aryl, heteroaryl, halogen,CN, CF₃, NR⁵ ₂, —C₁₋₄-alkyl, —S(O)₂R⁵ or —OR⁵, wherein R⁵⁰ is connectedto R² by a carbon atom.

A further embodiment (“Embodiment 60”) is the compound of embodiment 59,wherein R² is optionally substituted methylene-thiophen-2,5-diyl,phenylene-O— or thiophen-2-yl-5-methylene, wherein R⁵⁰ is connected tothe phenylene or thiophenyl group.

A further embodiment (“Embodiment 61”) is the compound of embodiments51, 52, 53, 54, 55, 56, 57, 58, 59 or 60, wherein D is selected from thegroup consisting of pyridinyl, thiazolyl, 1,3,4-thiadiazolyl,1,2,4-thiadiazolyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl,pyrazinyl, pyridazinyl, pyrimidinyl, benzothiazolyl and5,6-dihydro-4H-cyclopentathiazolyl, each optionally substituted with oneor two groups selected from halogen, CF₃, or optionally substitutedC₁₋₄-alkyl.

A further embodiment (“Embodiment 62”) is the compound of embodiment 61,wherein D is selected from the group consisting of thiazolyl,1,3,4-thiadiazolyl, and 1,2,4-thiadiazolyl, each optionally substitutedwith one or two groups selected from halogen, CF₃, or optionallysubstituted C₁₋₄-alkyl.

A further embodiment (“Embodiment 63”) is a pharmaceutical compositioncomprising a compound of any one of embodiments 1-62 and apharmaceutically acceptable excipient.

A further embodiment (“Embodiment 64”) is a method of treating,preventing, delaying the time to onset or reducing the risk for thedevelopment or progression of a disease or condition for which one ormore glucokinase activator is indicated, said method comprising the stepof administering to an animal a therapeutically effective amount of acompound of embodiments 1-62, compositions thereof, or pharmaceuticallyacceptable salts or prodrugs thereof

A further embodiment (“Embodiment 63”) is the method of embodiment 64,wherein said disease or condition is Type 1 diabetes.

A further embodiment (“Embodiment 64”) is the method of embodiment 64,wherein said disease or condition is Type 2 diabetes.

A further embodiment (“Embodiment 65”) is the method of embodiment 64,wherein said disease or condition is impaired glucose tolerance.

A further embodiment (“Embodiment 66”) is the method of embodiment 64,wherein said disease or condition is insulin resistance

A further embodiment (“Embodiment 67”) is the method of embodiment 64,wherein said disease or condition is hyperglycemia

A further embodiment (“Embodiment 68”) is the method of embodiment 64,wherein said disease or condition is postprandial hyperglycemia.

A further embodiment (“Embodiment 69”) is the method of embodiment 64,wherein said disease or condition is fasting hyperglycemia.

A further embodiment (“Embodiment 70”) is the method of embodiment 64,wherein said disease or condition is accelerated gluconeogenesis.

A further embodiment (“Embodiment 71”) is the method of embodiment 64,wherein said disease or condition is excessive hepatic glucose output.

A further embodiment (“Embodiment 72”) is the method of embodiment 64,wherein said disease or condition is hyperinsulinemia.

A further embodiment (“Embodiment 73”) is the method of embodiment 64,wherein said disease or condition is Metabolic Syndrome X.

Another aspect of the present invention are pharmaceutical compositionscomprising a compound of the present invention.

Another aspect of the present invention are single enantiomers ordiasteromers of a compound of the present invention.

Another aspect of the present invention are enantiomerically enrichedcompositions comprising an enantiomer of a compound of the presentinvention. In one embodiment, a single enantiomeris >60%, >70%, >80%, >85%, >90%, >91%, >92%, >93%, >94%, >95%, >96%, >97%, >98%or >99% enriched as compared to the total percentage of all otherenantiomers of the same compound present in the composition.

Another aspect provides for salts, including pharmaceutically acceptablesalts, of compounds of the present invention and pharmaceuticalcompositions comprising a pharmaceutically acceptable salt of thepresent invention. Salts of compounds of the present invention includean inorganic base addition salt such as sodium, potassium, lithium,calcium, magnesium, ammonium, aluminum salts or organic base additionsalts, or an inorganic acid addition salt such as HBr, HCl, sulfuric,nitric, or phosphoric acid addition salts or an organic acid additionsalt such as acetic, propionic, pyruvic, malanic, succinic, malic,maleic, fumaric, tartaric, citric, benzoic, methanesulfonic,ethanesulforic, stearic or lactic acid addition salt.

Another aspect provides for anhydrates, hydrates and solvates ofcompounds of the present invention and pharmaceutical compositionscomprising a pharmaceutically acceptable anhydrates, hydrates andsolvates of the present invention. Included are an anhydrate, hydrate orsolvate of a free form or salt of a compound of the present invention.Hydrates include, for example, a hemihydrate, monohydrate, dihydrate,trihydrate, quadrahydrate, pentahydrate, sesquihydrate.

Another aspect provides for the use of a compound of the presentinvention for the manufacture of a medicament for treating, preventing,delaying the time to onset or reducing the risk for the development orprogression of a disease or condition for which one or more glucokinaseactivator is indicated.

Another aspect provides for the use of a compound of the invention forthe manufacture of a medicament for treating, preventing, delaying thetime to onset or reducing the risk for the development or progression ofa disease or condition responsive to decreased hepatic glucoseproduction or responsive to lowered blood glucose levels, the methodcomprising the step of administering to an animal a therapeuticallyeffective amount a compound of the invention, or a pharmaceuticallyacceptable salt or prodrugs thereof.

Another aspect provides for methods of treating, preventing, delayingthe time to onset or reducing the risk for the development orprogression of a disease or condition for which one or more glucokinaseactivator is indicated.

Another aspect provides for methods of treating, preventing, delayingthe time to onset or reducing the risk for the development orprogression of a disease or condition responsive to decreased hepaticglucose production or responsive to lowered blood glucose levels, themethod comprising the step of administering to an animal atherapeutically effective amount a compound of the invention, or apharmaceutically acceptable salt or prodrugs thereof.

Another aspect provides for methods for treating, preventing, delayingthe time to onset or reducing the risk for the development orprogression of Type 1 diabetes, the method comprising the step ofadministering to an animal a therapeutically effective amount a compoundof the invention.

Another aspect provides for methods for treating, preventing, delayingthe time to onset or reducing the risk for the development orprogression of Type 1 diabetes, the method comprising the step ofadministering to an animal a therapeutically effective amount a compoundof the invention.

Another aspect provides for methods for treating, preventing, delayingthe time to onset or reducing the risk for the development orprogression of impaired glucose tolerance, the method comprising thestep of administering to an animal a therapeutically effective amount acompound of the invention.

Another aspect provides for methods for treating, preventing, delayingthe time to onset or reducing the risk for the development orprogression of insulin resistance, the method comprising the step ofadministering to an animal a therapeutically effective amount a compoundof the invention.

Another aspect provides for methods for treating, preventing, delayingthe time to onset or reducing the risk for the development orprogression of hyperglycemia, the method comprising the step ofadministering to an animal a therapeutically effective amount a compoundof the invention. In one embodiment, the hyperglycemia is postprandialhyperglycemia. In another embodiment, the hyperglycemia is fastinghyperglycemia.

Another aspect provides for methods for treating, preventing, delayingthe time to onset of or reducing the risk for the development orprogression of accelerated gluconcogenesis, the method comprising thestep of administering to an animal a therapeutically effective amount acompound of the invention.

Another aspect provides for methods for treating, preventing, delayingthe time to onset of or reducing the risk for the development orprogression of increased or excessive (greater than normal levels)hepatic glucose output, the method comprising the step of administeringto an animal a therapeutically effective amount a compound of theinvention.

Another aspect provides for methods for treating, preventing, delayingthe time to onset of or reducing the risk for the development orprogression of hyperinsulinemia, the method comprising the step ofadministering to an animal a therapeutically effective amount a compoundof the invention.

Another aspect provides for methods for treating, preventing, delayingthe time to onset of or reducing the risk for the development orprogression of hyperlipidemia, the method comprising the step ofadministering to an animal a therapeutically effective amount a compoundof the invention.

Another aspect provides for methods for treating, preventing, delayingthe time to onset of or reducing the risk for the development orprogression of dyslipidemia, the method comprising the step ofadministering to an animal a therapeutically effective amount a compoundof the invention.

Another aspect provides for methods for treating, preventing, delayingthe time to onset of or reducing the risk for the development orprogression of hypercholesterolemia, the method comprising the step ofadministering to an animal a therapeutically effective amount a compoundof the invention.

Other aspects provide for methods for treating, preventing, delaying thetime to onset of or reducing the risk for the development or progressionof atherosclerosis, obesity, or Metabolic Syndrome X, the methodcomprising the step of administering to an animal a therapeuticallyeffective amount a compound of the invention.

Formulations

In one aspect, compounds of the invention are administered in a totaldaily dose of 0.01 to 2500 mg. In one aspect the range is about 1 mg toabout 1000 mg. In one aspect the range is about 1 mg to about 500 mg. Inone aspect the range is about 10 mg to about 500 mg. The dose may beadministered in as many divided doses as is convenient or necessary.

In another aspect, compounds of the invention are administered in a unitdose of a range between 0.01 to 1000 mg. In one aspect the range isabout 0.1 mg to about 500 mg. In one aspect the range is about 0.1 mg toabout 100 mg. In one aspect the range is about 1 mg to about 1000 mg. Inone aspect the range is about 1 mg to about 500 mg. In one aspect therange is about 1 mg to about 100 mg. In one aspect the range is about 1mg to about 10 mg. In one aspect the range is about 10 mg to about 1000mg. In one aspect the range is about 10 mg to about 500 mg. In oneaspect the range is about 10 mg to about 100 mg. In one aspect, the unitdose is 10 mg. In one aspect, the unit dose is 25 mg. In one aspect, theunit dose is 50 mg. In one aspect, the unit dose is 75 mg. In oneaspect, the unit dose is 100 mg. In one aspect, the unit dose is 150 mg.In one aspect, the unit dose is 200 mg. In one aspect, the unit dose is250 mg. In one aspect, the unit dose is 300 mg. In one aspect, the unitdose is 400 mg. In one aspect, the unit dose is 500 mg. In one aspect,the unit dose is 600 mg. In one aspect, the unit dose is 700 mg. In oneaspect, the unit dose is 800 mg. In one aspect, the unit dose is 900 mg.In one aspect, the unit dose is 1000 mg.

In one aspect the compound is administered QD (once a day). In anotheraspect the compound is administered BID (twice a day). In another aspectthe compound is administered TID (three times a day). In another aspectthe compound is administered QID (four times a day). In one aspect thecompound is administered before a meal. In one aspect the compound isadministered after a meal. In one aspect the compound is administered inthe morning hours. In one aspect the compound is administered uponawaking in the morning. In one aspect the compound is administered inthe evening hours. In one aspect the compound is administered at bedtimein the evening.

Compounds of this invention may be used in combination with otherpharmaceutical agents. The compounds may be administered as a daily doseor an appropriate fraction of the daily dose (e.g., bid). Administrationof the compound may occur at or near the time in which the otherpharmaceutical agent is administered or at a different time. Thecompounds of this invention may be used in a multidrug regimen, alsoknown as combination or ‘cocktail’ therapy, wherein, multiple agents maybe administered together, may be administered separately at the sametime or at different intervals, or administered sequentially. Thecompounds of this invention may be administered after a course oftreatment by another agent, during a course of therapy with anotheragent, administered as part of a therapeutic regimen, or may beadministered prior to therapy by another agent in a treatment program.

For the purposes of this invention, the compounds may be administered bya variety of means including orally, parenterally, by inhalation spray,topically, or rectally in formulations containing pharmaceuticallyacceptable carriers, adjuvants and vehicles. The term parenteral as usedhere includes subcutaneous, intravenous, intramuscular, andintraarterial injections with a variety of infusion techniques.Intraarterial and intravenous injection as used herein includesadministration through catheters. Intravenous administration isgenerally preferred.

Pharmaceutically acceptable salts include acetate, adipate, besylate,bromide, camsylate, chloride, citrate, edisylate, estolate, fumarate,gluceptate, gluconate, glucoranate, hippurate, hyclate, hydrobromide,hydrochloride, iodide, isethionate, lactate, lactobionate, maleate,mesylate, methylbromide, methylsulfate, napsylate, nitrate, oleate,palmoate, phosphate, polygalacturonate, stearate, succinate, sulfate,sulfosalicylate, tannate, tartrate, terphthalate, tosylate, andtriethiodide.

Pharmaceutical compositions containing the active ingredient may be inany form suitable for the intended method of administration. When usedfor oral use for example, tablets, troches, lozenges, aqueous or oilsuspensions, dispersible powders or granules, emulsions, hard or softcapsules, syrups or elixirs may be prepared. Compositions intended fororal use may be prepared according to any method known to the art forthe manufacture of pharmaceutical compositions and such compositions maycontain one or more agents including sweetening agents, flavoringagents, coloring agents and preserving agents, in order to provide apalatable preparation. Tablets containing the active ingredient inadmixture with non-toxic pharmaceutically acceptable excipient which aresuitable for manufacture of tablets are acceptable. These excipients maybe, for example, inert diluents, such as calcium or sodium carbonate,lactose, calcium or sodium phosphate; granulating and disintegratingagents, such as maize starch, or alginic acid; binding agents, such asstarch, gelatin or acacia; and lubricating agents, such as magnesiumstearate, stearic acid or talc. Tablets may be uncoated or may be coatedby known techniques including microencapsulation to delay disintegrationand adsorption in the gastrointestinal tract and thereby provide asustained action over a longer period. One aspect relates to theadministration of a pharmaceutically acceptable composition of thepresent invention by controlled- or delayed-release means.Controlled-release pharmaceutical products have a common goal ofimproving drug therapy over that achieved by their non-controlledrelease counterparts.

A variety of known controlled- or extended-release dosage forms,formulations, and devices can be adapted for use with the crystallineforms of the invention. Examples include, but are not limited to, thosedescribed in U.S. Pat. Nos. 3,845,770; 3,916,899; 3,536,809; 3,598, 123;4,008,719; 5,674.533; 5,059,595; 5,591,767; 5,120,548; 5,073,543;5,639,476; 5,354,556; 5,733,566; and 6,365,185, each of which isincorporated herein by reference.

These dosage forms can be used to provide delayed or controlled-releaseof one or more active ingredients using, for example,hydroxypropylmethyl cellulose, other polymer matrices, gels, permeablemembranes, osmotic systems (such as OROS, Alza Corporation, MountainView, Calif. USA), multilayer coatings, microparticles, liposomes, ormicrospheres or a combination thereof to provide the desired releaseprofile in varying proportions. Additionally, ion exchange materials canbe used to prepare immobilized, adsorbed co-crystals and thus effectcontrolled delivery of the drug. Examples of specific anion exchangersinclude, but are not limited to, Duolite A568 and Duolite AP143 (Rohm &Haas, Spring House, Pa., USA).

One aspect of the invention encompasses a unit dosage form whichcomprises a pharmaceutically acceptable composition comprising acrystalline form of a compound of the present invention and one or morepharmaceutically acceptable excipients or diluents, wherein thepharmaceutical composition, medicament or dosage forms is formulated forcontrolled-release. In another aspect, the dosage form utilizes anosmotic drug delivery system.

A particular and well-known osmotic drug delivery system is referred toas OROS (Alza Corporation, Mountain View, Calif. USA). This technologycan readily be adapted for the delivery of compounds and compositions ofthe invention. Various aspects of the technology are disclosed in U.S.Pat. Nos. 6,375,978; 6,368,626; 6,342,249; 6,333,050; 6,287,295;6,283,953; 6,270,787; 6,245,357; and 6,132,420; each of which isincorporated herein by reference. Specific adaptations of OROS that canbe used to administer compounds and compositions of the inventioninclude, but are not limited to, the OROS; Push-Pull, Delayed Push-Pull,Multi-Layer Push-Pull, and Push-Stick Systems, all of which are wellknown. See, e.g., www.alza.com. Additional OROS systems that can be usedfor the controlled oral delivery of compounds and compositions of theinvention include OROS-CT and L-OROS (Id.; see also, Delivery Times,vol. II, issue II (Alza Corporation).

Conventional OROS oral dosage forms are made by compressing a drugpowder (e.g. a crystalline form selected from Forms A-D) into a hardtablet, coating the tablet with cellulose derivatives to form asemi-permeable membrane, and then drilling an orifice in the coating(e.g., with a laser). Kim, Cherug-ju, Controlled Release Dosage FormDesign, 231-238 (Technomic Publishing, Lancaster, Pa.: 2000). Theadvantage of such dosage forms is that the delivery rate of the drug isnot influenced by physiological or experimental conditions. Even a drugwith a pH-dependent solubility can be delivered at a constant rateregardless of the pH of the delivery medium. But because theseadvantages are provided by a build-up of osmotic pressure within thedosage form after administration, conventional OROS drug deliverysystems cannot be used to effectively deliver drugs with low watersolubility. Id. at 234.

A specific dosage form of the invention comprises: a wall defining acavity, the wall having an exit orifice formed or formable therein andat least a portion of the wall being semipermeable; an expandable layerlocated within the cavity remote from the exit orifice and in fluidcommunication with the semipermeable portion of the wall; a dry orsubstantially dry state drug layer located within the cavity adjacent tothe exit orifice and in direct or indirect contacting relationship withthe expandable layer; and a flow-promoting layer interposed between theinner surface of the wall and at least the external surface of the druglayer located within the cavity, wherein the drug layer comprises acrystalline form of a compound of the present invention. See U.S. Pat.No. 6,368,626, the entirety of which is incorporated herein byreference.

Another specific dosage form of the invention comprises: a wall defininga cavity, the wall having an exit orifice formed or formable therein andat least a portion of the wall being semipermeable; an expandable layerlocated within the cavity remote from the exit orifice and in fluidcommunication with the semipermeable portion of the wall; a drug layerlocated within the cavity adjacent the exit orifice and in direct orindirect contacting relationship with the expandable layer; the druglayer comprising a liquid, active agent formulation absorbed in porousparticles, the porous particles being adapted to resist compactionforces sufficient to form a compacted drug layer without significantexudation of the liquid, active agent formulation, the dosage formoptionally having a placebo layer between the exit orifice and the druglayer, wherein the active agent formulation comprises a crystalline formof a compound of the present invention. See U.S. Pat. No. 6,342,249, theentirety of which is incorporated herein by reference.

In another aspect, a pharmaceutical composition or medicament comprisinga crystalline form of a compound of the present invention isadministered transdermally. Such a transdermal (TD) delivery can avoidfirst-pass metabolism. Additionally, a “pill-and-patch” strategy can betaken, where only a fraction of the daily dose is delivered through theskin to generate basal systemic levels, onto which oral therapy isadded.

Formulations for oral use may be also presented as hard gelatin capsuleswhere the active ingredient is mixed with an inert solid diluent, forexample calcium phosphate or kaolin, or as soft gelatin capsules whereinthe active ingredient is mixed with water or an oil medium, such aspeanut oil, liquid paraffin or olive oil.

Aqueous suspensions of the invention contain the active materials inadmixture with excipients suitable for the manufacture of aqueoussuspensions. Such excipients include a suspending agent, such as sodiumcarboxymethylcellulose, methylcellulose, ethylcellulose,hydroxypropylcellulose, hydroxypropyl methylcellulose, sodium alginate,polyvinylpyrrolidone, gum tragacanth and gum acacia, and dispersing orwetting agents such as a naturally occurring phosphatide (e.g.,lecithin), a condensation product of an alkylene oxide with a fatty acid(e.g., polyoxyethylene stearate), a condensation product of ethyleneoxide with a long chain aliphatic alcohol (e.g.,heptadecaethyleneoxycetanol), a condensation product of ethylene oxidewith a partial ester derived from a fatty acid and a hexitol anhydride(e.g., polyoxyethylene sorbitan monooleate). The aqueous suspension mayalso contain one or more preservatives such as ethyl or n-propylp-hydroxy-benzoate, one or more coloring agents, one or more flavoringagents and one or more sweetening agents, such as sucrose or saccharin.

Oil suspensions may be formulated by suspending the active ingredient ina vegetable oil, such as arachid oil, olive oil sesame oil or coconutoil, or in a mineral oil such as liquid paraffin. The oral suspensionsmay contain a thickening agent, such as beeswax, hard paraffin or cetylalcohol. Sweetening agents, such as those set forth above, and flavoringagents may be added to provide a palatable oral preparation. Thesecompositions may be preserved by the addition of an antioxidant such asascorbic acid.

Dispersible powders and granules of the invention suitable forpreparation of an aqueous suspension by the addition of water providethe active ingredient in admixture with a dispersing or wetting agent, asuspending agent, and one or more preservatives. Suitable dispersing orwetting agents and suspending agents are exemplified by those disclosedabove. Additional excipients, for example sweetening, flavoring andcoloring agents, may also be present.

The pharmaceutical compositions of the invention may also be in the formof oil-in-water emulsions. The oily phase may be a vegetable oil, suchas olive oil or arachid oil, a mineral oil, such as liquid paraffin, ora mixture of these. Suitable emulsifying agents includenaturally-occurring gums, such as gum acacia and gum tragacanth,naturally occurring phosphatides, such as soybean lecithin, esters orpartial esters derived from fatty acids and hexitol anhydrides, such assorbitan monooleate, and condensation products of these partial esterswith ethylene oxide, such as polyoxyethylene sorbitan monooleate. Theemulsion may also contain sweetening and flavoring agents.

Syrups and elixirs may be formulated with sweetening agents, such asglycerol, sorbitol or sucrose. Such formulations may also contain ademulcent, a preservative, a flavoring or a coloring agent.

The pharmaceutical compositions of the invention may be in the form of asterile injectable preparation, such as a sterile injectable aqueous oroleaginous suspension. This suspension may be formulated according tothe known art using those suitable dispersing or wetting agents andsuspending agents which have been mentioned above. The sterileinjectable preparation may also be a sterile injectable solution orsuspension in a non-toxic parenterally acceptable diluent or solvent,such as a solution in 1,3-butane-diol or prepared as a lyophilizedpowder. Among the acceptable vehicles and solvents that may be employedare water, Ringer's solution and isotonic sodium chloride solution. Inaddition, sterile fixed oils may conventionally be employed as a solventor suspending medium. For this purpose any bland fixed oil may beemployed including synthetic mono- or diglycerides. In addition, fattyacids such as oleic acid may likewise be used in the preparation ofinjectables.

As noted above, formulations of the present invention suitable for oraladministration may be presented as discrete units such as capsules,cachets or tablets each containing a predetermined amount of the activeingredient; as a powder or granules; as a solution or a suspension in anaqueous or non-aqueous liquid; or as an oil-in-water liquid emulsion ora water-in-oil liquid emulsion. The active ingredient may also beadministered as a bolus, electuary or paste.

A tablet may be made by compression or molding, optionally with one ormore accessory ingredients. Compressed tablets may be prepared bycompressing in a suitable machine the active ingredient in a freeflowing form such as a powder or granules, optionally mixed with abinder (e.g., povidone, gelatin, hydroxypropylmethyl cellulose),lubricant, inert diluent, preservative, disintegrant (e.g., sodiumstarch glycolate, cross-linked povidone, cross-linked sodiumcarboxymethyl cellulose) surface active or dispersing agent. Moldedtablets may be made by molding in a suitable machine a mixture of thepowdered compound moistened with an inert liquid diluent. The tabletsmay optionally be coated or scored and may be formulated so as toprovide slow or controlled release of the active ingredient thereinusing, for example, hydroxypropyl methylcellulose in varying proportionsto provide the desired release profile. Tablets may optionally beprovided with an enteric coating, to provide release in parts of the gutother than the stomach. This is particularly advantageous with thecompounds of Formula 1 when such compounds are susceptible to acidhydrolysis.

Formulations suitable for topical administration in the mouth includelozenges comprising the active ingredient in a flavored base, usuallysucrose and acacia or tragacanth; pastilles comprising the activeingredient in an inert base such as gelatin and glycerin, or sucrose andacacia; and mouthwashes comprising the active ingredient in a suitableliquid carrier.

Formulations for rectal administration may be presented as a suppositorywith a suitable base comprising for example cocoa butter or asalicylate.

Formulations suitable for vaginal administration may be presented aspessaries, tampons, creams, gels, pastes, foams or spray formulationscontaining in addition to the active ingredient such carriers as areknown in the art to be appropriate.

Formulations suitable for parenteral administration include aqueous andnon-aqueous isotonic sterile injection solutions which may containantioxidants, buffers, bacteriostats and solutes which render theformulation isotonic with the blood of the intended recipient; andaqueous and non-aqueous sterile suspensions which may include suspendingagents and thickening agents. The formulations may be presented inunit-dose or multi-dose sealed containers, for example, ampoules andvials, and may be stored in a freeze-dried (lyophilized) conditionrequiring only the addition of the sterile liquid carrier, for examplewater for injections, immediately prior to use. Injection solutions andsuspensions may be prepared from sterile powders, granules and tabletsof the kind previously described.

Formulations suitable for parenteral administration may be administeredin a continuous infusion manner via an indwelling pump or via a hospitalbag. Continuous infusion includes the infusion by an external pump. Theinfusions may be done through a Hickman or PICC or any other suitablemeans of administering a formulation either parenterally or i.v.

Preferred unit dosage formulations are those containing a daily dose orunit, daily sub-dose, or an appropriate fraction thereof, of a drug.

It will be understood, however, that the specific dose level for anyparticular patient will depend on a variety of factors including theactivity of the specific compound employed; the age, body weight,general health, sex and diet of the individual being treated; the timeand route of administration; the rate of excretion; other drugs whichhave previously been administered; and the severity of the particulardisease undergoing therapy, as is well understood by those skilled inthe art.

EXAMPLES: SYNTHESIS OF COMPOUNDS OF THE INVENTION

Compounds of Formula I and Formula II can be prepared according to themethodology outlined in the following general synthetic schemes or withmodifications of these schemes that will be evident to persons skilledin the art.

Synthesis of the Phosphonate Prodrug Compounds of the Invention 1)Preparation of a Phosphonate Prodrug

Prodrugs can be introduced at different stages of the synthesis. Mostoften these prodrugs are made from the phosphonic acids of compounds ofthe invention because of their lability. Phosphonic acids of compoundsof the invention can be alkylated with electrophiles such as alkylhalides and alkyl sulfonates under nucleophilic substitution conditionsto give phosphonate esters. For example, acyloxyalkyl prodrugs ofcompounds of the invention can be prepared by direct alkylation ofcompounds of Formula I with an appropriate acyloxyalkyl halide (e.g.,Cl, Br, I; Phosphorus Sulfur 54:143 (1990); Synthesis 62 (1988)) in thepresence of a suitable base (e.g., pyridine, TEA, diisopropylethylamine)in suitable solvents such as DMF (J. Med. Chem. 37:1875 (1994)). Thecarboxylate component of these acyloxyalkyl halides includes but is notlimited to acetate, propionate, isobutyrate, pivalate, benzoate,carbonate and other carboxylates.

Dimethylformamide dialkyl acetals can also be used for the alkylation ofphosphonic acids (Collect. Czech Chem. Commu. 59:1853 (1994)). Compoundsof the invention wherein the prodrug moiety comprises a cycliccarbonate, a lactone or a phthalidyl group can also be synthesized bydirect alkylation of the free phosphonic acids with appropriate halidesin the presence of a suitable base such as NaH or diisopropylethylamine(J. Med. Chem. 38:1372 (1995); J. Med. Chem. 37:1857 (1994); J. Pharm.Sci. 76:180 (1987)).

Alternatively, these phosphonate prodrugs can be synthesized by thereactions of the corresponding dichlorophosphonate and an alcohol(Collect Czech Chem. Commun. 59:1853 (1994)). For example, adichlorophosphonate is reacted with substituted phenols and arylalkylalcohols in the presence of a base such as pyridine or TEA to give thecompounds of the invention wherein the prodrug moiety is an aryl group(J, Med. Chem. 39:4109 (1996); J. Med. Chem. 38:1372 (1995); J. Med.Chem. 37:498 (1994)) or an arylalkyl group (J. Chem. Soc. Perkin Trans.1 38:2345 (1992)). The disulfide-containing prodrugs (Antiviral Res.22:155 (1993)) can be prepared from a dichlorophosphonate and2-hydroxyethyldisulfide under standard conditions. Dichlorophosphonatesare also useful for the preparation of various phosphonamides asprodrugs. For example, treatment of a dichlorophosphonate with ammoniagives both a monophosphonamide and a diphosphonamide; treatment of adichlorophosphonate with 1-amino-3-propanol gives a cyclic1,3-propylphosphonamide; treatment of a chlorophosphonate monophenylester with an amino acid ester in the presence of a suitable base givesa substituted monophenyl monophosphonamidate.

Such reactive dichlorophosphonates can be generated from thecorresponding phosphonic acids with a chlorinating agent (e.g., thionylchloride, J. Med. Chem. 1857 (1994); oxalyl chloride, Tetrahedron Len.31:3261 (1990); phosphorous pentachloride, Synthesis 490 (1974)).Alternatively, a dichlorophosphonate can be generated from itscorresponding disilyl phosphonate esters (Synth. Commu. 17:1071 (1987))or dialkyl phosphonate esters (Tetrahedron Lett. 24:4405 (1983); Bull.Soc. Chim. 130:485 (1993)). Compounds of the invention can be mixedphosphonate ester (e.g., phenyl and benzyl esters, or phenyl andacyloxyalkyl esters) including the chemically combined mixed esters suchas phenyl and benzyl combined prodrugs reported in Bioorg. Med. Chem.Lett. 7:99 (1997).

Dichlorophosphonates are also useful for the preparation of variousphosphonamides as prodrugs. For example, treatment of adichlorophosphonate with an amine (e.g. an amino acid alkyl ester suchas L-alanine ethyl ester) in the presence of a suitable base (e.g.triethylamine, pyridine, etc.) gives the corresponding bisphosphonamide;treatment of a dichlorophosphonate with 1-amino-3-propanol gives acyclic 1,3-propylphosphonamide; treatment of a chlorophosphonatemonophenyl ester with an amino acid ester in the presence of a suitablebase gives a substituted monophenyl monophosphonamidate. Directcouplings of a phosphonic acid with an amine (e.g. an amino acid alkylester such as L-alanine ethyl ester) are also reported to give thecorresponding bisamidates under Mukaiyama conditions (J. Am. Chem. Soc.,94:8528 (1972)).

The SATE (S-acetyl thioethyl) prodrugs can be synthesized by thecoupling reaction of the phosphonic acid compounds of the invention andS-acyl-2-thioethanol in the presence of DCC, EDCI or PyBOP (J. Med.Chem. 39.1981 (1996)).

Cyclic phosphonate esters of substituted 1,3-propane diols can besynthesized by either reactions of the corresponding dichlorophosphonatewith a substituted 1,3-propanediol or coupling reactions using suitablecoupling reagents (e.g., DCC, EDCI, PyBOP; Synthesis 62 (1988)). Thereactive dichlorophosphonate intermediates can be prepared from thecorresponding acids and chlorinating agents such as thionyl chloride (J.Med. Chem. 1857 (1994)), oxalyl chloride (Tetrahedron Lett. 31:3261(1990)) and phosphorus pentachloride (Synthesis 490 (1974)).Alternatively, these dichlorophosphonates can also be generated fromdisilyl esters (Synth. Commun. 17:1071 (1987)) and dialkyl esters(Tetrahedron Lett. 24:4405 (1983); Bull. Soc. Chim. Fr., 130:485(1993)).

Alternatively, these cyclic phosphonate esters of substituted1,3-propane diols are prepared from phosphonic acids by coupling withdiols under Mitsunobu reaction conditions (Synthesis 1 (1981); J. Org.Chem. 52:6331 (1992)), and other acid coupling reagents including, butnot limited to, carbodiimides (Collect. Czech. Chem. Commun. 59:1853(1994); Bioorg. Med. Chem. Lett. 2:145 (1992); Tetrahedron Lett. 29:1189(1988)), and benzotriazolyloxytris-(dimethylamino) phosphonium salts(Tetrahedron Lett. 34:6743 (1993)).

Phosphonic acids also undergo cyclic prodrug formation with cyclicacetals or cyclic ortho esters of substituted propane-1,3-diols toprovide prodrugs as in the case of carboxylic acid esters (Helv. Chim.Acta. 48:1746 (1965)). Alternatively, more reactive cyclic sulfites orsulfates are also suitable coupling precursors to react with phosphonicacid salts. These precursors can be made from the corresponding diols asdescribed in the literature.

Alternatively, cyclic phosphonate esters of substituted 1,3-propanediols can be synthesized by trans esterification reaction withsubstituted 1,3-propane diol under suitable conditions. Mixed anhydridesof parent phosphonic acids generated in situ under appropriateconditions react with diols to give prodrugs as in the case ofcarboxylic acid esters (Bull. Chem. Soc. Jpn. 52:1989 (1979)). Arylesters of phosphonates are also known to undergo transesterificationwith alkoxy intermediates (Tetrahedron Lett. 38:2597 (1997); Synthesis968 (1993)).

One aspect of the present invention provides methods to synthesize andisolate single isomers of prodrugs of compounds of the invention thatare phosphonic acids. Because phosphorus is a stereogenic atom,formation of a prodrug with a substituted-1,3-propane-diol will producea mixture of isomers. For example, formation of a prodrug with a racemic1-(V)-substituted-1,3-propane diol gives a racemic mixture ofcis-prodrugs and a racemic mixture of trans-prodrugs. In an otheraspect, the use of the enantioenriched substituted-1,3-propane diol withthe R-configuration gives enantioenriched R-cis- and R-trans-prodrugs.These compounds can be separated by a combination of columnchromatography and/or fractional crystallization.

The compounds of the invention can be mixed phosphonate esters (e.g.phenyl benzyl phosphonate esters, phenyl acyloxyalkyl phosphonateesters, phenyl aminoacid esters etc). For example, the chemicallycombined phenyl-benzyl prodrugs are reported by Meier, et al. Bioorg.Med. Chem. Lett., 1997, 7: 99.

The substituted cyclic propyl phosphonate esters compounds of theinvention, can be synthesized by reaction of the correspondingdichlorophosphonate and the substituted 1,3-propane diol. The followingare non-limiting methods to prepare the substituted 1,3-propane diols.

Synthesis of the 1,3-Propane Diols Used in the Preparation of CertainProdrugs

The discussion of this step includes various synthetic methods for thepreparation of the following types of propane-1,3-diols: i)1-substituted; ii) 2-substituted; and iii) 1,2- or 1,3-annulated.Different groups on the prodrug part of the molecule i.e., on thepropane diol moiety can be introduced or modified either during thesynthesis of the diols or after the synthesis of the prodrugs.

i) 1-Substituted 1,3-propanediols

1,3-Propanediols useful in the synthesis of compounds in the presentinvention can be prepared using various synthetic methods. As describedin Scheme A, additions of an aryl Grignard to a 1-hydroxy-propan-3-algive 1-aryl-substituted 1,3-propanediols (path a). This method issuitable for the conversion of various aryl halides to1-arylsubstituted-1,3-propanediols (J. Org. Chem. 1988, 53, 911).Conversions of aryl halides to 1-substituted 1,3-propanediols can alsobe achieved using Heck reactions (e.g., couplings with a 1,3-diox-4-ene)followed by reductions and subsequent hydrolysis reactions (TetrahedronLett. 1992, 33, 6845). Various aromatic aldehydes can also be convertedto 1-substituted-1,3-propanediols using alkenyl Grignard additionreactions followed by hydroboration-oxidation reactions (path b).

Aldol reactions between an enolate (e.g., lithium, boron, tin enolates)of a carboxylic acid derivative (e.g., tert-butyl acetate) and analdehyde (e.g., the Evans's aldol reactions) are especially useful forthe asymmetric synthesis of enantioenriched 1,3-propanediols. Forexample, reaction of a metal enolate of t-butyl acetate with an aromaticaldehyde followed by reduction of the ester (path e) gives a1,3-propanediol (J. Org. Chem. 1990, 55 4744). Alternatively,epoxidation of cinnamyl alcohols using known methods (e.g., Sharplessepoxidations and other asymmetric epoxidation reactions) followed byreduction reactions (e.g., using Red-Al) give various 1,3-propanediols(path c). Enantioenriched 1,3-propanediols can be obtained viaasymmetric reduction reactions (e.g., enantioselective boranereductions) of 3-hydroxy-ketones (Tetrahedron Lett. 1997, 38 761).Alternatively, resolution of racemic 1,3-propanediols using variousmethods (e.g., enzymatic or chemical methods) can also giveenantioenriched 1,3-propanediol. Propan-3-ols with a 1-heteroarylsubstituent (e.g., a pyridyl, a quinolinyl or an isoquinolinyl) can beoxygenated to give 1-substituted 1,3-propanediols using N-oxideformation reactions followed by a rearrangement reaction in aceticanhydride conditions (path d) (Tetrahedron 1981, 37, 1871).

ii) 2-Substituted 1,3-propanediols

A variety of 2-substituted 1,3-propanediols useful for the synthesis ofcompounds of Formula I can be prepared from various other1,3-propanediols (e.g., 2-(hydroxymethyl)-1,3-propanediols) usingconventional chemistry (Comprehensive Organic Transformations, VCH, NewYork, 1989). For example, as described in Scheme B, reductions of atrialkoxycarbonylmethane under known conditions give a triol viacomplete reduction (path a) or a bis(hydroxymethyl)acetic acid viaselective hydrolysis of one of the ester groups followed by reduction ofthe remaining two other ester groups. Nitrotriols are also known to givetriols via reductive elimination (path b) (Synthesis 1987, 8, 742).Furthermore, a 2-(hydroxymethyl)-1,3-propanediol can be converted to amono acylated derivative (e.g., acetyl, methoxycarbonyl) using an acylchloride or an alkyl chloroformate (e.g., acetyl chloride or methylchloroformate) (path d) using known chemistry (Protective Groups InOrganic Synthesis; Wiley, New York, 1990). Other functional groupmanipulations can also be used to prepare 1,3-propanediols such asoxidation of one the hydroxymethyl groups in a2-(hydroxymethyl)-1,3-propanediol to an aldehyde followed by additionreactions with an aryl Grignard (path c). Aldehydes can also beconverted to alkyl amines via reductive amination reactions (path e).

iii) Annulated 1,3-Propane Diols

Compounds of invention wherein V and Z or V and W are connected by fourcarbons to form a ring can be prepared from a 1,3-cyclohexanediol. Forexample, cis, cis-1,3,5-cyclohexanetriol can be modified to give variousother 1,3,5-cyclohexanetriols which are useful for the preparations ofcompounds of Formula I wherein R⁵¹ and R⁵¹ together are

wherein together V and W are connected via 3 atoms to form a cyclicgroup containing 6 carbon atoms substituted with a hydroxy group. It isenvisioned that these modifications can be performed either before orafter formation of a cyclic phosphonate 1,3-propanediol ester. Various1,3-cyclohexanediols can also be prepared using Diels-Alder reactions(e.g., using a pyrone as the diene: Tetrahedron Lett. 1991, 32, 5295).2-Hydroxymethylcyclohexanol and 2-hydroxymethylcyclopentanols are usefulfor the preparations of compounds of the invention wherein R⁵¹ and R⁵¹together are

wherein together V and Z are connected via 2 or 3 atoms to form a cyclicgroup containing 5 or 6 carbon atoms. 1,3-Cyclohexanediol derivativesare also prepared via other cycloaddition reaction methodologies. Forexample, cycloadducts from the cycloaddition reactions of a nitrileoxide and an olefin can be converted to a 2-ketoethanol derivative whichcan be further converted to a 1,3-propanediol (including1,3-cyclohexanediol, 2-hydroxymethylcyclohexanol and2-hydroxymethylcyclopentanol) using known chemistry (J. Am. Chem. Soc.1985, 107, 6023). Alternatively, precursors to 1,3-cyclohexanediol canbe made from quinic acid (Tetrahedron Lea. 1991, 32. 547.)

Generation of Phosphonic Acid

Select compounds may be prepared from phosphonate esters using knownphosphate and phosphonate ester cleavage conditions. In general, silylhalides have been used to cleave the various phosphonate esters,followed by mild hydrolysis of the resulting silyl phosphonate esters togive the desired phosphonic acids. Depending on the stability of theproducts, these reactions are usually accomplished in the presence ofacid scavengers such as 1,1,1,3,3,3-hexamethyldisilazane, 2,6-lutidine,etc. Such silyl halides include, chlorotrimethylsilane (Rabinowitz, J.Org. Chem., 1963, 28: 2975), bromotrimethylsilane (McKenna, et al,Tetrahedron Lett., 1977, 155), iodotrimethylsilane (Blackburn, et al, J.Chem. Soc., Chem. Commun., 1978, 870). Alternately, phosphonate esterscan be cleaved under strong acid conditions, (e.g HBr, HCl, etc.) inpolar solvents, preferably acetic acid (Moffatt, et al, U.S. Pat. No.3,524,846, 1970) or water. These esters can also be cleaved viadichlorophosphonates, prepared by treating the esters with halogenatingagents e.g. phosphorus pentachloride, thionyl chloride, BBr₃, etc.(Pelchowicz, et al, J. Chem. Soc., 1961, 238) followed by aqueoushydrolysis to give phosphonic acids. Aryl and benzyl phosphonate esterscan be cleaved under hydrogenolysis conditions (Lejczak, et al,Synthesis, 1982, 412; Elliott, et al, J. Med. Chem., 1985, 28: 1208;Baddiley, et al, Nature, 1953, 171: 76) or dissolving metal reductionconditions (Shafer, et al, J. Am. Chem. Soc., 1977, 99: 5118).Electrochemical (Shono, et al, J. Org. Chem., 1979, 44: 4508) andpyrolysis (Gupta, et al, Synth. Commun., 1980, 10: 299) conditions havealso been used to cleave various phosphonate esters.

Synthesis of the Phosphinate and Phosphonate Monoester Prodrug Compoundsof the Invention

1) Preparation of Phosphinate and Phosphonate Monoester Prodrug

Phosphinic acids and phosphonic acid monoesters can be alkylated withelectrophiles such as alkyl halides and alkyl sulfonates undernucleophilic substitution conditions to give phosphinate and phosphonateester prodrugs. For example, compounds of Formulas I and II whereinY²R⁵¹ is an acyloxyalkyl group can be prepared by direct alkylation ofcompounds of Formulas I and II wherein Y²R⁵¹ is OH with an appropriateacyloxyalkyl halide (e.g., Cl, Br, I; Phosphorus Sulfur 54:143 (1990);Synthesis 62 (1988)) in the presence of a suitable base (e.g., pyridine,TEA, diisopropylethylamine) in suitable solvents such as DMF (J. Med.Chem. 37:1875 (1994)). The carboxylate component of these acyloxyalkylhalides includes but is not limited to acetate, propionate, isobutyrate,pivalate, benzoate, carbonate and other carboxylates.

Dimethylformamide dialkyl acetals can also be used for the alkylation ofphosphinic acids and phosphonic acid monoesters (Collect. Czech Chem.Commu. 59:1853 (1994)). Compounds of Formulas I and II wherein Y²R⁵¹ isa cyclic carbonate, a lactone or a phthalidyl group can also besynthesized by direct alkylation of the free phosphonic acids withappropriate halides in the presence of a suitable base such as NaH ordiisopropylethylamine (J. Med. Chem. 38:1372 (1995); J. Med. Chem.37:1857 (1994); J. Pharm. Sci. 76:180 (1987)).

Alternatively, these phosphinate and phosphonate monoester prodrugs canbe synthesized by the reactions of the correspondingchlorophospho(i)nate and an alcohol (Collect Czech Chem. Commun. 59:1853(1994)). For example, a chlorophospho(i)nate is reacted with substitutedphenols and arylalkyl alcohols in the presence of a base such aspyridine or TEA to give the compounds of Formula I wherein YR⁵¹ is anaryl group (J. Med. Chem. 39:4109 (1996): J. Med. Chem. 38:1372 (1995);J. Med. Chem. 37:498 (1994)) or an arylalkyl group (J. Chem. Soc. PerkinTrans. 1 38:2345 (1992)). The disulfide-containing prodrugs (AntiviralRes. 22:155 (1993)) can be prepared from a chlorophospho(i)nate and2-hydroxyethyldisulfide under standard conditions. Chlorophospho(i)natesare also useful for the preparation of various phospho(i)namides asprodrugs. For example, treatment of a chlorophospho(i)nate with ammoniagives the phospho(i)namide.

Such reactive chlorophospho(i)nates can be generated from thecorresponding phosphinic acids and phosphonic acid monoesters with achlorinating agent (e.g., thionyl chloride, J. Med. Chem. 1857 (1994);oxalyl chloride, Tetrahedron Len. 31:3261 (1990); phosphorouspentachloride, Synthesis 490 (1974)). Alternatively, achlorophospho(i)nate can be generated from its corresponding silylphosphinate ester or phosphonic acid monester (Synth. Commu. 17:1071(1987)) or alkyl phosphinate esters (Tetrahedron Lett. 24:4405 (1983);Bull Soc. Chim. 130:485 (1993)).

Chlorophospho(i)nates are also useful for the preparation of variousphosphonamides as prodrugs. For example, treatment of achlorophospho(i)nate with an amine (e.g. an amino acid alkyl ester suchas L-alanine ethyl ester) in the presence of a suitable base (e.g.triethylamine, pyridine, etc.) gives the corresponding phospho(i)namide.Direct couplings of phosphinic acids or phosphonic acid monoesters withan amine (e.g. an amino acid alkyl ester such as L-alanine ethyl ester)are also reported to give the corresponding amidate under Mukaiyamaconditions (J. Am. Chem. Soc. 94:8528 (1972)).

The SATE (S-acetyl thioethyl) prodrugs can be synthesized by thecoupling reaction of the phosphinic acids or phosphonic acid monoestersof Formulas I and II and S-acyl-2-thioethanol in the presence of DCC,EDCI or PyBOP (J. Med. Chem. 39:1981 (1996)).

2) Generation of Phosphonic Acid Monoesters

Compounds of Formulas I and II wherein R⁵⁰ is —P(O)(Y²R⁵¹)(OR³) and R³is C₁-C₆alkyl may be prepared from the diester intermediate, used forthe synthesis of phosphonic acid, by monosaponification. Monohydrolysisof one of the ester groups on the phosphonate may be accomplished bytreatment of phosphonate diesters with aqueous alkaline solution such asNaOH, KOH or LiOH at rt or while heating. Sodium azide can also be usedin DMF (Bioorg. Med. Chem. Lett 14(13), 3559-62 (2004)) to accomplishedthe monosaponification. Alternatively, organic bases such as morpholineor N-methyl-piperazine can be used to hydrolyze one of the phosphonateester groups (Synth. Comm. 34(2):331-344 (2004)).

3) Generation of Phosphinic Acids

The introduction of a phosphinic acid group can generally beaccomplished according to known methods. An efficient way to synthesizephosphinic acid is to convert a phosphonate diester to its correspondingmonochloridate-monoester using one of many chlorinating agents such asPCl₅(Can. J. Chem. 76(3):313-18 (1998)), oxalyl chloride (TetrahedronLett. 44(12):1445-48 (2003)), thionyl chloride (J. Med. Chem.45(4):919-29 (2002)) or phosgene (Redcl. Trav. Chim. Pays-Bas 78:59-61(1959)) and to introduce the carbon-based substituent on the phosphorusatom via a Grignard reagent (J. Chem. Soc. Perkin Trans. 1 17:2179-86(1996)), a lithium anion (J. Med. Chem. 33(11):2952-56 (1990)) or anenolate (Bioorg Med. Chem. 5(7):1327-38 (1997)) to produce the desiredphosphinate ester. The phosphinic acid is then generated bysaponification with aqueous NaOH, KOH or LiOH or using one of the manymethods known to deprotect phosphonic acids such as TMSBr or TMSCl/KI.Alternatively, phosphinic acids can be generated from phosphonic acidmonoesters by making the monochloridate-monoester with chlorinatingreagents such as thionyl chloride or oxalyl chloride, and introducingthe substituent on the phosphorus as above.

Other methods include palladium-catalyzed cross-coupling of alkylphosphinates to form H-phosphinate esters (Tetrhedron 61(26):6315-6329(2005)), based-promoted alkylation of H-phosphinate esters withelectrophiles (J. Org. Chem. 72(8):2851-2856(2007)), andpalladium-catalyzed cross-coupling of (low alkyl)phosphinic acid esterwith aryl halides and aryl triflates (J. Org. Chem.63(10):3463-3467(1998); Synthesis (14):2216-2220(2003); Synthesis(9):778-780(1984)).

Cyclic phosphinic acids can be synthesized starting from a1,2-dicarboxylate-benzene precursor (J. Am. Chem. Soc. 101:7001-08(1979)) which is reduced to the di-benzylic alcohol and brominated withPBr₃ to give the di-benzylic bromide precursor (Synth. Commun.14(6):507-514 (1984)). Double Arbuzov condensation of the di-benzylicbromide with bis(trimethylsilyloxy)phosphine, made from the reaction ofammonium hypophosphite and hexamethyldisilazane, provides the cyclicphosphinate ester (J. Org. Chem. 60:6076-81 (1995)) which can beconverted to the phosphinic acid by saponification with NaOH or TMSBr.Alternatively, the di-benzyl bromide precursor can be obtained bybromination of a substituted 1,2-dimethyl benzene with bromine orN-bromosuccinimide (J. Chem. Soc. 3358-61 (1959)) or directbromomethylation by reacting formaldehyde and HBr in presence of aceticacid (J. Phys. Chem. 108(4):5145-55 (2004)).

The following examples are provided so that the invention can be morefully understood and should not be construed as limiting the inventionin any way.

Hydrogen atoms on both carbon and heteroatoms may be implied on chemicalstructures within.

Examples: Synthesis of Compounds of Formula I

Compounds of Formula I can be prepared according to the processesdescribed in the following representative Schemes. Reagents andconditions given are only for illustration purposes and alternativemethods may be employed by those skilled in the art. It should beunderstood that the following Schemes do not limit the invention whichis defined by the claims. Typically the synthesis of a compound ofFormula I includes the following general steps: (1) deprotection of aphosphonate or phosphinate ester; (2) introduction of a phosphonate orphosphinate; (3) formation of the amide bond; (4) preparation of thearyl or heteroaryl carboxylic acid; (5) construction of the aryl orheteroaryl carboxylic ester. The order of introduction of a phosphonateor phosphinate group and the formation of the amide bond in thesynthesis of compounds of Formula I can be freely decided by thoseskilled in the art based on the structure of the substrate. Variablegroups in Schemes have the same meanings defined for Formula I unlessstated otherwise. In all applicable structures contained in the Schemesdescribed in this invention, P¹ is a protecting group such asC₁₋₄-alkyl; P² is alkyl or cycloalkyl; P³ is a leaving group such as F,Cl, Br, I, or triflate; P⁴ is P³, —P(O)(OP¹)₂, or —P(O)(OP¹)P²; P⁵ isaryl, heteroaryl, alkyl, cycloalkyl, or arylalkyl; X′ is X or afunctional group that can be transformed into X; and Y′ is R or afunctional group that can be transformed into R². Protection anddeprotection in the Schemes may be carried out according to theprocedures generally known in the art (e.g., T. W. Greene and P. G. M.Wuts, “Protecting Groups in Organic Synthesis”, 3^(rd) edition, JohnWiley & Sons, 1999).

Deprotection of a Phosphonate or Phosphinate Ester

Compounds of Formula I wherein R⁵⁰ is —P(O)(OH)₂ or —P(O)(OH)P² may beprepared from phosphonate or phosphinate esters using the known cleavagemethods. Silyl halides are generally used to cleave various phosphonateor phosphinate esters and give the desired phosphonic or phosphinic acidupon mild hydrolysis of the resulting phosphonate or phosphinate silylesters. When needed, acid scavengers (e.g., HMDS) can be used for theacid sensitive compounds. Representative conditions can be found in theGeneration of phospho(i)nic acid section in this publication. Methods toform phosphonate monoesters can be found in the Generation of PhosphonicAcid Monoesters section in this publication.

Introduction of a Phosphonate or Phosphinate Estr

The introduction of a phosphonate or phosphinate group generally can beaccomplished according to known procedures. Compounds of Formula 1wherein D is nitrogen-containing heteroarylene may be prepared by anumber of known methods (Scheme 2). For example, the coupling reactionof a phenyl bromide (J. Org. Chem. 1999, 64, 120), iodide (PhosphorusSulfur 1997, 130, 59) or triflate (J. Org. Chem. 2001, 66, 348) withdiethyl phosphite or diisopropyl phosphite in the presence of apalladium catalyst is widely used within the art. Alkylphosphinic acidisopropyl ester or alkylphosphinic acid ethyl ester may be used in theaforementioned procedures to afford the desired alkylphosphinate esters.Other methods such as Michaelis-Arbuzov reaction (Chem. Rev. 1981, 81,415) can also be used to introduce the phosphonate group by coupling abenzyl, arylalkyl, or heteroarylalkyl halide/triflate with triethylphosphite or triisopropyl phosphite. Lithiated heteroaryl ring carboncan react with dialklyl chlorophosphate to attach the phosphonate groupto the corresponding heteroaryl ring.

Formation of an Amide Bond

Standard amide bond formation methods can be used to couple amino groupswith carboxylic acids or activated derivatives thereof. For example, (i)reactions of an amine with a carboxylic acid in the presence of DCC orEDC according to the known methods (e.g., J. Org. Chem. 1977, 42, 2019);(ii) conversion of a carboxylic group to an acid chloride by reactionwith oxalyl chloride, followed by coupling the acid chloride with anamine in the presence of a base (e.g. triethyl amine or pyridine) inchloroform or DCM (Org. Synth., Collect Vol. V, 1973, 336); (iii) otherknown procedures (Tetrahedron Lett. 1990, 31, 7119; Tetrahedron Lett.1989, 30, 6917; J. Org. Chem. 1993, 58, 618).

Preparation of the Aryl or Heteroaryl Carboxylic Acid

Deprotection reactions of carboxylic esters are well known in the art.Methyl or ethyl ester is deprotected in the presence of sodium hydroxideor lithium hydroxide in a mixture of THF/EtOH/water (e.g., TetrahedronLett. 1977, 3529). Benzyl ester is removed using hydrogenolysisconditions (e.g., Org. React. 1953, VII, 263).

Construction of the Aryl or Heteroaryl Carboxylic Ester

Processes for the synthesis of compounds 7 are provided according totheir substitution patterns. Syntheses of compounds 7a generally followsimilar synthetic processes as those of compounds 7.

Compounds 7 wherein G¹=G²=G³=CH can be prepared by a number of knownmethods:

(i) When X is aryl, heteroaryl, alkyl, cycloalkyl, or arylalkyl, theinstallation of X′ can be accomplished by Stille couplings (J. Am. Chem.Soc. 1984, 106, 4630; Tetrahedron Lett. 1995, 36, 2191), Suzukicouplings (Chem. Rev. 1995, 95, 2457), Friedel-Crafts alkylations(Synlett 1996, 557), or Negishi couplings (Org. Lett., 2003, 5, 423) asdescribed in Scheme 5.

(ii) When X is aryloxy, heteroaryloxy, alkyloxy, cycloalkyloxy orarylalkyloxy, the installation of O—P⁵ can be accomplished by Mitsunobureactions (Org. Prep. Proceed. Int. 1996, 28, 127), displacementreactions (J. Org. Chem. 2006, 71, 2170: Synthesis 2004, 2625), orcoupling reactions (J. Am. Chem. Soc. 2003, 125, 9032) as described inScheme 6.

(iii) When R² is the group -E²-E³, wherein E² is a direct bond or analkylene, the installation of Y′ can be accomplished by Stille couplings(J. Am. Chem. Soc. 1984, 106, 4630; Tetrahedron Lett. 1995, 36, 2191),Suzuki couplings (Chem. Rev. 1995, 95, 2457), Friedel-Crafts alkylations(Synlett 1996, 557), or Negishi couplings (Org. Lett., 2003, 5, 423) asdescribed in Scheme 7.

(iv) When R² is the group -E¹-E²-E³, wherein E¹ is O, the installationof O—P⁵ can be accomplished by Mitsunobn reactions (Org. Prep. Proceed,km 1996, 28, 127), displacement, reactions (J. Org. Chem, 2006, 71,2170; Synthesis 2004, 2625), or coupling reactions (J. Am. Chem. Soc.2003, 125, 9032) as described in Scheme 8.

(v) When R² is the group -E¹-E²-E³, wherein E¹ is S, the installation ofS—P⁵ can be accomplished by Pd₂(dba)₃, CuBr, or CuI catalyzed reactions(Tetrahedron 2001, 57, 3069; Tetrahedron Lett. 2000, 41, 1283; Synlett2004, 1254; Org. Let. 2002, 4, 3517), or displacement reactions asdescribed in Scheme 9.

Compounds 7 wherein G²=N and G¹=G³=CH can be prepared by a number ofknown methods:

(i) When X is aryl, heteroaryl, alkyl, cycloalkyl, or arylalkyl, theinstallation of X′ can be accomplished by either Stille couplings (J.Am. Chem. Soc. 1984, 106, 4630; Tetrahedron Lett. 1995, 36, 2191) orSuzuki couplings (Chem. Rev. 1995, 95, 2457) as described in Scheme 10.

(ii) When X is aryloxy, heteroaryloxy, alkyloxy, cycloalkyloxy orarylalkyloxy, the installation of O—P⁵ can be accomplished bydisplacement reaction as described in Scheme 11.

(iii) When Y is the group -E²-E³, wherein E² is a direct bond or analkylene, the installation of Y′ can be accomplished by either Stillecouplings (J. Am. Chem. Soc. 1984, 106, 4630; Tetrahedron Lett. 1995,36, 2191) or Suzuki couplings (Chem. Rev. 1995, 95, 2457) as describedin Scheme 12.

(iv) When Y is the group -E¹-E²-E³, wherein E¹ is O, the installation ofO—P⁵ can be accomplished by displacement reaction as described in Scheme13.

Examples: Synthesis of Compounds of Formula II

Compounds of Formula II can be prepared according to the processesdescribed in the following representative Schemes. Reagents andconditions given are only for illustration purposes and alternativemethods may be employed by those skilled in the art. It should beunderstood that the following Schemes do not limit the invention whichis defined by the claims. Typically the synthesis of a compound ofFormula II includes the following general steps: (1) deprotection of aphosphonate or phosphinate ester; (2) formation of the amide bond; (3)preparation of the aryl or heteroaryl carboxylic acid; (4) constructionof the aryl or heteroaryl carboxylic ester; (5) introduction of aphosphonate or phosphinate. The timing of introducing a phosphonate orphosphinate group in the synthesis of compounds of Formula II can befreely decided by those skilled in the art based on the structure of thesubstrate. Variable groups in Schemes have the same meanings defined forFormula II unless stated otherwise. In all applicable structurescontained in the Schemes described in this invention, P¹ is a protectinggroup such as C₁₋₄-alkyl; P² is alkyl or cycloalkyl; P³ is a leavinggroup such as F, Cl, Br, I, or triflate; P⁵ is aryl, heteroaryl, alkyl,cycloalkyl, or arylalkyl; X′ is X or a functional group that can betransformed into X: Y″ is R²-R⁵⁰ or a functional group that can betransformed into R²-R⁵⁰; Y1 is arylene, alkylene, heteroarylene,cycloalkylene, or arylalkylene; Y1′ is Y1-R⁵⁰ or a functional group thatcan be transformed into Y1-R⁵⁰. Protection and deprotection in theSchemes may be carried out according to the procedures generally knownin the art (e.g., T. W. Greene and P. G. M. Wuts, “Protecting Groups inOrganic Synthesis”, 3^(rd) edition, John Wiley & Sons, 1999).

Deprotection of a Phosphonate or Phosphinate Ester

Compounds of Formula II wherein R⁵⁰ is —P(O)(OH)₂ or —P(O)(OH)P² may beprepared from phosphonate or phosphinate esters using the known cleavagemethods. Silyl halides are generally used to cleave various phosphonateor phosphinate esters and give the desired phosphonic or phosphinic acidupon mild hydrolysis of the resulting phosphonate or phosphinate silylesters. When needed, acid scavengers (e.g., HMDS) can be used for theacid sensitive compounds. Such silyl halides include TMSCl (J. Org.Chem. 1963, 28, 2975), TMSBr (Tetrahedron Lett. 1977, 155) and TMSI (J.Chem. Soc., Chem. Commun. 1978, 870). Aryl and benzyl phosphonate orphosphinate esters can be cleaved under hydrogenolysis conditions(Synthesis 1982, 412; J. Med. Chem. 1985, 28, 1208) or metal reductionconditions (J. Chem. Soc. 1977, 99, 5188). Electrochemical (J. Org.Chem. 1979, 44, 4508) and pyrolysis (Synth. Commun. 1980, 10, 299)conditions have been used to cleave various phosphonate esters.

Formation of an Amide Bond

Standard amide bond formation methods can be used to couple amino groupswith carboxylic acids or activated derivatives thereof. For example, (i)reactions of an amine with a carboxylic acid in the presence of DCC orEDC according to the known methods (e.g., J. Org. Chem. 1977, 42, 2019);(ii) conversion of a carboxylic group to an acid chloride by reactionwith oxalyl chloride, followed by coupling the acid chloride with aminein the presence of a base (e.g. triethyl amine or pyridine) inchloroform or DCM (Org. Synth., Collect Vol. V, 1973, 336); (iii) otherknown procedures (Tetrahedron Lett. 1990, 31, 7119; Tetrahedron Lett.1989, 30, 6917; J Org. Chem. 1993, 58, 618).

Preparation of the Aryl or Heteroaryl Carboxylic Acid

Deprotection reactions of esters are well known in the art. Methyl orethyl ester is deprotected in the presence of sodium hydroxide orlithium hydroxide in a mixture of THF/EtOH/water (e.g., TetrahedronLett. 1977, 3529). Benzyl ester is removed using hydrogenolysiscondition (e.g., Org. React 1953, VII, 263).

Construction of the Aryl or Heteroaryl Carboxylic Ester

Processes for the synthesis of compounds 14 are provided according totheir substitution patterns. Syntheses of compounds 14a generally followsimilar synthetic processes as those of compounds 14.

Compounds 14 wherein G¹=G²=G³=CH can be prepared by a number of knownmethods:

(i) When X is aryl, heteroaryl, alkyl, cycloalkyl, or arylalkyl, theinstallation of X′ can be accomplished by Stille couplings (J. Am. Chem.Soc. 1984, 106, 4630; Tetrahedron Lett. 1995, 36, 2191), Suzukicouplings (Chem. Rev. 1995, 95, 2457), Friedel-Crafts alkylations(Synlett 1996, 557), or Negishi couplings (Org. Lett., 2003, 5, 423) asdescribed in Scheme 17.

(ii) When X is aryloxy, heteroaryloxy, alkyloxy, cycloalkyloxy orarylalkyloxy, the installation of O—P⁵ can be accomplished by Mitsunobureactions (Org. Prep. Proceed. Int. 1996, 28, 127), displacementreactions (J. Org. Chem. 2006, 71, 2170; Synthesis 2004, 2625), orcoupling reactions (J. Am. Chem. Soc. 2003, 125, 9032) as described inScheme 18.

(iii) When R² is the group -E³-E⁴-, wherein E³ is arylene,heteroarylene, alkylene, or cycloalkylene, the installation of Y″ can beaccomplished by Stille couplings (J. Am. Chem. Soc. 1984, 106, 4630;Tetrahedron Len. 1995, 36, 2191), Suzuki couplings (Chem. Rev. 1995, 95,2457), Friedel-Crafts alkylations (Synlett 1996, 557), or Negishicouplings (Org. Lett., 2003, 5, 423) as described in Scheme 19.

(iv) When R² is the group -E¹-E²-E³-E⁴-, wherein E¹ is O, theinstallation of O—Y1′ can be accomplished by Mitsunobu reactions (Org.Prep. Proceed Int. 1996, 28, 127), displacement reactions (J. Org. Chem.2006, 71, 2170; Synthesis 2004, 2625), or coupling reactions (J. Am.Chem. Soc. 2003, 125, 9032) as described in Scheme 20.

(v) When Y is the group -E¹-E²-E³-E⁴-, wherein E¹ is S, the installationof S—Y1′ can be accomplished by either Pd₂(dba)₃, CuBr, or CuI catalyzedreactions (Tetrahedron 2001, 57, 3069; Tetrahedron Let. 2000, 41, 1283;Synlett 2004, 1254; Org. Let. 2002, 4, 3517) or displacement reactionsas described in Scheme 21.

Introduction of a Phosphonate or Phosphinate Ester

In general the introduction of a phosphonate or phosphinate group can beaccomplished according to known procedures. Compounds of Formula II,wherein the phosphorous-containing group is directly attached to anarylene or a nitrogen-containing heteroarylene, may be prepared by anumber of known methods. For example, the coupling reaction of a phenylbromide (J. Org. Chem. 1999, 64, 120), iodide (Phosphorus Sulfur 1997,130, 59) or triflate (J. Org. Chem. 2001, 66, 348) with diethylphosphite or diisopropyl phosphite in the presence of a palladiumcatalyst is widely used within the art. Alkylphosphinic acid isopropylester or alkylphosphinic acid ethyl ester may be used in theaforementioned procedures to afford the desired alkylphosphinate esters.Functionalized arylphosphinates may be prepared according to a knownprocedure (Tetrahedron Lent. 1996, 37, 1651)

Compounds of Formula II, wherein the phosphonate is directly attached toan alkylene linker, may be prepared by a number of known methods. Forexample, Michaelis-Arbuzov reaction (Chem. Rev. 1981, 81, 415) can alsobe used to introduce the phosphonate group by coupling an alkyl, benzyl,arylalkyl, or heteroarylalkyl halide/triflate with triethyl phosphite ortriisopropyl phosphite.

Compounds of Formula II, wherein the phosphorous-containing group is anH-phosphinic acid can be formed according to literature procedures(Tetrahedron Lett. 1992, 33, 813; J. Orgnomet. Chem 2005, 690, 2388;Tetrahedron 2005, 61, 6315). These H-phosphinic acid derivatives can bealkylated to give the corresponding alkylphosphonates according to knownprocedures (Synthesis 1985, 896; Synthesis 1986, 240; Phosphorus Sulfur1996, 115, 255; J. Am. Chem. Soc. 1996, 118, 10168; J. Am. Chem. Soc.2002, 124, 3842).

Example 1{6-[3-Isopropoxy-5-(2-thiophen-3-yl-ethoxy)-benzoylamino]-pyridin-3-yl}-methylphosphinicacid

To a solution of{6-[3-isopropoxy-5-(2-thiophen-3-yl-ethoxy)-benzoylamino]-pyridin-3-yl}-methyl-phosphinicacid ethyl ester (469 mg, 0.960 mmol) in DCM (10 mL) was added HMDS(1.62 mL, 7.68 mmol) and TMSBr (0.51 mL, 3.84 mmol) at rt. Stirred at rtovernight. TMSI (0.07 mL, 0.480 mmol) was added to the milky mixture onthe second day. Stirred at rt for 1.5 hr. The mixture was concentrated,re-dissolved in EtOAc (10 mL), and filtered through a 0.4 μm syringefilter to remove insoluble NH₄Br. The filtrate was concentrated and theresidue was dissolved in MeOH (10 mL), stirred at rt for 3 hr, andconcentrated again. The resulting residue was partitioned between EtOAcand water. After layers were separated, the aqueous layer was extractedwith EtOAc (2×). Combined EtOAc layers were washed with brine (1×),dried with anhydrous MgSO4, filtered, and concentrated to give{6-[3-Isopropoxy-5-(2-thiophen-3-yl-ethoxy)-benzoylamino]-pyridin-3-yl}-methylphosphinicacid (242 mg, 53%) as a yellow foam. ¹H NMR (300 MHz, DMSO-d₆): δ 11.08(br, 1H), 8.68 (ddd, J=6, 2, 1 Hz, 1H), 8.32 (m, 1H), 8.14 (m, 1H), 7.51(dd, J=5, 3 Hz, 1H), 7.36 (dd, J=3, 2 Hz, 1H), 7.24 (m, 1H), 7.20 (m,1H), 7.15 (dd, J=5, 1 Hz, 1H), 6.71 (m, 1H), 4.77 (m, 1H), 4.28 (m, 2H),3.11 (m, 2H). 1.58 (d, J=15 Hz, 3H), 1.30 (d, J=6 Hz, 6H); LC-MS (m/z):461.3 [C23H25N2O5PS+H]⁺. Anal. Calcd. for (C23H25N2O5PS+1.1H₂O): C,55.02; H, 5.71; N, 5.83. Found: C, 55.02; H, 5.31; N. 5.44.

Intermediates for the preparation of Example 1 were prepared accordingto Route 1, as described below.

Route 1

Step A 3-Hydroxy-5-isopropoxy-benzoic acid methyl ester

To a stirred solution of methyl 3,5-dihydroxybenzoate (20.0 g, 119 mmol)in acetone (500 mL) was added K₂CO₃ (19.7 g, 143 mmol) and 2-iodopropane(13.1 mL, 131 mmol) at rt. The resulting mixture was refluxed for 12 hr.Then the mixture was filtered through a pad of Celite to removeinsoluble salts and the cake was rinsed with acetone. Combined filtrateswere concentrated under vacuum to afford a residue which was purified bysilica gel flash chromatography (7.5×30 cm, hexane/EtOAc, v/v 10:1,5:1). Fractions containing the mono-alkylation product were pooled andconcentrated to give 3-hydroxy-5-isopropoxy-benzoic acid methyl ester(11.1 g, 44%) as a white solid. ¹H NMR (300 MHz, CDCl₃): δ 7.11-7.14 (m,2H), 6.60 (m, 1H), 4.56 (m, 1H), 3.89 (s, 3H), 1.32 (d, J=6 Hz, 6H).

Step B 3-Isopropoxy-5-(2-thiophen-3-yl-ethoxy)-benzoic acid methyl ester

To a stirred solution of 3-hydroxy-5-isopropoxy-benzoic acid methylester (3.76 g, 17.9 mmol) in THF (100 mL) at rt was added PPh₃ (4.93 g,18.8 mmol) and 2-(3-thienyl)ethanol (2.10 mL, 18.8 mmol). DIAD (3.71 mL,18.8 mmol) was added dropwise at rt with external cooling to keep thesolvent from boiling off. The resulting mixture was stirred at rt for 3hr and concentrated to give a residue which was purified by silica gelchromatography (5×25 cm, hexane/EtOAc, v/v=10:1, 5:1). Fractionscontaining the product were pooled and concentrated to give3-isopropoxy-5-(2-thiophen-3-yl-ethoxy)-benzoic acid methyl ester (5.24g, 91%) as a yellow oil. ¹H NMR (300 MHz, CDCl₃): δ 7.28 (dd, J=5, 3 Hz,1H), 7.15-7.18 (m, 2H), 7.08-7.09 (m, l), 7.03 (dd, J=5, 1 Hz, 1H), 6.63(m, 1H), 4.58 (m, 1H), 4.19 (t, J=7 Hz, 2H). 3.89 (s, 3H). 3.12 (t, J=7Hz, 2H), 1.33 (d, J=6 Hz, 6H).

Step C 3-Isopropoxy-5-(2-thiophen-3-yl-ethoxy)-benzoic acid

To a solution of 3-isopropoxy-5-(2-thiophen-3-yl-ethoxy)-benzoic acidmethyl ester (5.24 g, 16.4 mmol) in THF (120 mL) was added EtOH (80 mL)and water (40 mL) at rt. Sodium hydroxide solution (1.0 M, 49.1 mL) wasadded slowly with some external cooling if needed. The mixture wasstirred at rt overnight. On the second day organic solvents were removedby evaporation. The residue was partitioned between ether and water.After the ether layer was discarded, the aqueous layer was acidifiedwith HCl (6.0 M, −8.2 mL) to pH<1, and extracted with EtOAc (3×).Combined EtOAc layers were washed with brine (1×), dried with anhydrousMgSO₄, filtered, and concentrated to give3-isopropoxy-5-(2-thiophen-3-yl-ethoxy)-benzoic acid (4.54 g, 90%) as awhite solid. ¹H NMR (300 MHz, CDCl₃): δ 7.29 (dd, J=5, 3 Hz, 1H),7.22-7.24 (m, 2H), 7.09-7.10 (m, 1H), 7.04 (dd, J=5, 1 Hz, 1H), 6.69 (m,1H), 4.59 (m, 1H), 4.21 (t, J=7 Hz, 2H), 3.14 (t, J=7 Hz, 2H), 1.35 (d,J=6 Hz, 6H).

Step DN-(5-Bromo-pyridin-2-yl)-3-isopropoxy-5-(2-thiophen-3-yl-ethoxy)-benzamide

To a solution of 3-isopropoxy-5-(2-thiophen-3-yl-ethoxy)-benzoic acid(2.5 g, 8.16 mmol) in DCM (50 mL) was added (COCl)₂ (1.42 mL, 16.3 mmol)and DMF (0.06 mL, 0.816 mmol) at rt. After stirring at rt for 1.5 hr,the mixture was concentrated. The resulting residue was azeotroped with50 mL anhydrous toluene and then re-dissolved in DCM (40 mL), cooled to0° C. A solution of pyridine and 2-amino-5-bromo-pyridine in DCM (10 mL)was added slowly to the reaction flask. The resulting mixture wasstirred at rt overnight. On second day solvents were removed and theresidue was partitioned between EtOAc and water. The organic layer wasseparated, washed with brine (1×), dried with anhydrous MgSO₄, filtered,and concentrated. The residue was purified by silica gel flashchromatography (6×25 cm, hexane/EtOAc, v/v=10:1, 5:1, 3:1). Fractionscontaining the coupling product were pooled and concentrated to giveN-(5-bromo-pyridin-2-yl)-3-isopropoxy-5-(2-thiophen-3-yl-ethoxy)-benzamide(3.78 g, 90%) as a yellow foam. ¹H NMR (300 MHz, CDCl₃): δ 8.56 (br,1H), 8.30-8.33 (m, 2H), 7.85 (dd, J=9, 3 Hz, 1H), 7.29 (dd, J=5, 3 Hz,1H), 7.09-7.10 (m, 1H), 7.03 (dd, J=5, 1 Hz, 1H), 6.97-7.00 (m, 2H),6.63 (m, 1H), 4.59 (m, 1H), 4.21 (t, J=7 Hz, 2H), 3.14 (t, J=7 Hz, 2H),1.35 (d, J=6 Hz, 6H).

Step E{6-[3-Isopropoxy-5-(2-thiophen-3-yl-ethoxy)-benzoylamino]-pyridin-3-yl}-methyl-phosphinicacid ethyl ester

To a stirred solution ofN-(5-bromo-pyridin-2-yl)-3-isopropoxy-5-(2-thiophen-3-yl-ethoxy)-benzamide(1.69 g, 3.66 mmol) in toluene (40 mL) was added a solution ofmethylphosphinic acid ethyl ester (0.475 g, 4.40 mmol), palladiumtetrakis(triphenylphosphine) (0.846 g, 0.733 mmol), and Et₃N (1.54 mL,10.9 mmol) in DCM (5.0 mL) at rt. The mixture was heated at 90° C.overnight. Cooled to rt and concentrated. EtOAc and water were added andthe mixture was filtered through a pad of Celite to remove the insolublesolids. The organic layer was separated, washed with brine (1×), driedwith anhydrous MgSO₄, filtered, and concentrated. The residue waspurified by silica gel flash chromatography (6×25 cm, hexane/EtOAc,v/v=1:3, EtOAc. 1% MeOH in EtOAc). Fractions containing the product werepooled and concentrated to give{6-[3-Isopropoxy-5-(2-thiophen-3-yl-ethoxy)-benzoylamino]-pyridin-3-yl}-methyl-phosphinicacid ethyl ester (1.65 g, 92%) as a yellow oil. ¹H NMR (300 MHz, CDCl₃):δ 8.74 (br, 1H), 8.68 (ddd, J=6, 2, 1 Hz, 1H), 8.49 (ddd, J=9, 2, 1 Hz,1H), 8.10 (ddd, J=11, 9, 2 Hz, 1H), 7.63-7.70 (m, 1H), 7.43-7.47 (m,1H), 7.29 (dd, J=5, 3 Hz, 1H), 7.09-7.10 (m, 1H), 7.04 (dd, J=5.1 Hz,1H), 6.99-7.03 (m, 2H), 6.64 (m, 1H), 4.60 (m, 1H), 4.22 (t, J=7 Hz,2H), 4.07-4.15 (m, 1H), 3.84-3.92 (m, 1H), 3.14 (t, J=7 Hz, 2H), 1.70(d, J=15 Hz, 3H), 1.35 (d, J=6 Hz, 6H), 1.23-1.31 (m, 3H).

Example 2{6-[3-isopropoxy-5-(2-thiophen-3-yl-ethoxy)-benzoylamino]-pyridin-3-ylmethyl}-phosphonicacid hydrochloride

{6-[3-Isopropoxy-5-(2-thiophen-3-yl-ethoxy)-benzoylamino]-pyridin-3-ylmethyl}-phosphonicacid diethyl ester (86.0 mg, 0.166 mmol) was dissolved in DCM (0.8 mL)and cooled to −78° C. TMSBr (0.21 mL, 1.61 mmol) was added and thereaction mixture was allowed to warm to rt over 24 hours. The reactionmixture was concentrated under reduced pressure and partitioned indiethyl ether (5 mL) and 1N aqueous sodium hydroxide (5 mL). The aqueouslayer was rinsed twice with diethyl ether (5 mL), then acidified to pH=1with concentrated hydrochloric acid and extracted with EtOAc (3×5 mL).The organic layer dried over sodium sulfate, filtered, and concentratedto give the title compound,{6-[3-isopropoxy-5-(2-thiophen-3-yl-ethoxy)-benzoylamino]-pyridin-3-ylmethyl}-phosphonicacid hydrochloride (16.6 mg, 21.6% yield), as a pale brown foam. ¹H NMR(300 MHz, DMSO-d₆): δ 10.70 (s, 1H), 8.20 (s, 1H), 8.05 (d, J=6.0 Hz,1H), 7.70 (d, J=6.0 Hz, 1H), 7.45 (d, J=3.0 Hz, 1H), 7.30 (s, 1H), 7.20(s, 1H), 7.15 (s, 1H), 7.10 (d, J=3.0 Hz, 1H), 6.65 (s, 1H), 4.70 (m,1H), 4.25 (t, 2H), 3.10 (t, 2H), 2.95 (d, J=12.0 Hz, 2H), 1.25 (s, 6H);LCMS (m/z): 477.1 [C22H25N2O6PS+H]⁺. Anal. Calcd. for (C22H25N2O6PS+1.2HCl): C, 50.79; H, 5.08; N, 5.38. Found: C, 50.72; H, 4.91; N, 4.80.

Intermediates for the preparation of Example 2 were prepared accordingto Route 2, as described below.

Route 2

Step A 5-(tert-Butyl-dimethyl-silanyloxymethyl)-pyridin-2-ylamine

(6-Amino-pyridin-3-yl)-methanol (1.00 g, 8.06 mmol) was dissolved in amixture of DCM DMF (v/v 4:1, 50 mL) with stirring, and cooled to 0° C.N,N-diisopropylethylamine (1.99 mL, 12.09 mmol),tert-butyl-chloro-dimethyl-silane (1.67 g, 11.1 mmol) and4-dimethylaminopyridine (0.02 g, 0.16 mmol) were added. Stirred at rtfor 20 hours. The reaction mixture was concentrated under rotaryevaporation and partitioned in EtOAc (30 mL) and water (30 mL). Theorganic layer was rinsed with water (20 mL), and then a saturated sodiumchloride solution (20 mL), dried over sodium sulfate, filtered, andconcentrated to yellow oil. After chromatography on silica gel with agradient from 10-100% ethyl acetate-hexanes,5-(tert-butyl-dimethyl-silanyloxymethyl)-pyridin-2-ylamine (1.71 g,89.0% yield) was obtained as white crystals. ¹H NMR (300 MHz, DMSO-d₆):δ 7.78 (s, 1H), 7.35 (d, J=6.0 Hz, 1H), 6.35 (d, J=6.0 Hz, 1H), 5.80 (s,2H), 4.45 (s, 2H), 0.80 (s, 9H), 0.00 (s, 6H); LCMS (m/z): 239.4[C12H22N2OSi+H]⁺.

Step BN-[5-(tert-Butyl-dimethyl-silanyloxymethyl)-pyridin-2-yl]-3-isopropoxy-5-(2-thiophen-3-yl-ethoxy)-benzamide

3-Isopropoxy-5-(2-thiophen-3-yl-ethoxy)-benzoic acid (2.03 g, 6.61 mmol)was dissolved in DCM (33 mL) with DMF (0.05 mL), and cooled to 0° C.Oxalyl chloride (1.16 mL, 13.22 mmol) was added dropwise and the mixturewas allowed to stir for 1.5 hours. The reaction mixture was concentratedunder reduced pressure to remove residual oxalyl chloride. The yellowoil was re-dissolved in DCM (33 mL), and5-(tert-butyl-dimethyl-silanyloxymethyl)-pyridin-2-ylamine (1.71 g, 7.17mmol) and pyridine (0.86 mL, 10.5 mmol) were added. After 16 hours, thereaction mixture was concentrated under reduced pressure and partitionedin EtOAc (50 mL) and water (50 mL). The organic layer was rinsed withwater (30 mL), and then a saturated sodium chloride solution (30 mL),dried over sodium sulfate, filtered, and concentrated to brown oil.After chromatography on silica gel with a gradient from 5-30% ethylacetate-hexanes,N-[5-(tert-butyl-dimethyl-silanyloxymethyl)-pyridin-2-yl]-3-isopropoxy-5-(2-thiophen-3-yl-ethoxy)-benzamide(1.25 g, 36.0% yield) was obtained. ¹H NMR (300 MHz, DMSO-d₆): δ 10.65(s, 1H), 8.25 (s, 1H), 8.05 (d, J=6.0 Hz, 1H), 7.65 (d, J=6.0 Hz, 1H),7.40 (d, J=3.0 Hz, 1H), 7.25 (s, 1H), 7.15 (s, 1H), 7.10 (s, 1H), 7.05(d, J=3.0 Hz, 1H), 6.60 (s, 1H), 4.65 (s, 2H), 4.60 (m, 1H), 4.15 (t,2H), 2.95 (t, 2H), 1.05 (s, 3H), 1.0 (s, 3H), 0.85 (s, 9H), 0.00 (s,6H); LCMS (m/z): 527.3 [C28H38N2O4SSi+H]⁺.

Step CN-(5-Hydroxymethyl-pyridin-2-yl)-3-isopropoxy-5-(2-thiophen-3-yl-ethoxy)-benzamide

N-[5-(tert-Butyl-dimethyl-silanyloxymethyl)-pyridin-2-yl]-3-isopropoxy-5-(2-thiophen-3-yl-ethoxy)-benzamide(1.25 g, 2.37 mmol) was dissolved in THF (12 mL) and cooled to 0° C.Tetrabutylammonium fluoride (1.0 M solution in THF, 3.08 mL, 3.08 mmol)was added dropwise and the mixture was allowed to warm to rt over 24hours. The reaction mixture was concentrated under reduced pressure andpartitioned in EtOAc (30 mL) and water (30 mL). The organic layer wasrinsed with water (20 mL), and then a saturated sodium chloride solution(20 mL), dried over sodium sulfate, filtered, and concentrated to yellowoil. After chromatography on silica gel with a gradient from 15-100%ethyl acetate-hexanes,N-(5-hydroxymethyl-pyridin-2-yl)-3-isopropoxy-5-(2-thiophen-3-yl-ethoxy)-benzamide(0.73 g, 74.9% yield) was obtained as a colorless oil. 1H NMR (300 MHz,DMSO-d₆): δ 10.75 (s, 1H), 8.30 (s, 1H), 8.10 (d, J=6.0 Hz, 1H), 7.75(d, J=6.0 Hz, 1H), 7.45 (d, J=3.0 Hz, 1H), 7.30 (s, 1H), 7.20 (s, 1H),7.15 (s, 1H), 7.10 (d, J=3.0 Hz, 1H), 6.65 (s, 1H), 5.25 (t, 1H), 4.70(m, 1H), 4.50 (d, J=3.0 Hz, 2H), 4.25 (t, 2H), 3.05 (t, 2H), 1.25 (s,6H); LCMS (m/z): 413.1 [C22H24N2O4S+H]⁺.

Step DN-(5-Bromomethyl-pyridin-2-yl)-3-isopropoxy-5-(2-thiophen-3-yl-ethoxy)-benzamide

N-(5-Hydroxymethyl-pyridin-2-yl)-3-isopropoxy-5-(2-thiophen-3-yl-ethoxy)-benzamide(0.79 g, 1.92 mmol) in THF (10 mL) was added to a solution oftriphenylphosphine (1.03 g, 3.84 mmol) and carbon tetrabromide (1.27 g.3.84 mmol) in diethyl ether (10 mL). After 16 hours, the reactionmixture was concentrated under reduced pressure and partitioned in EtOAc(30 mL) and water (30 mL). The organic layer was rinsed with water (20mL), and then a saturated sodium chloride solution (20 mL), dried oversodium sulfate, filtered, and concentrated to yellow oil. Afterchromatography on silica gel with a gradient from 5-100% ethylacetate-hexanes,N-(5-bromomethyl-pyridin-2-yl)-3-isopropoxy-5-(2-thiophen-3-yl-ethoxy)-benzamide(0.92 g, 101.3% yield) was obtained, including some impurity, but wasused as-is. 1H NMR (300 MHz, DMSO-d₆): δ 10.85 (s, 1H), 8.45 (s, 1H),8.15 (d, J=6.0 Hz, 1H), 7.90 (d, J=6.0 Hz, 1H), 7.45 (d, J=3.0 Hz, 1H),7.30 (s, 1H), 7.20 (s, 1H), 7.15 (s, 1H), 7.10 (d, J=3.0 Hz, 1H), 6.65(s, 1H), 4.75 (s, 2H), 4.70 (m, 1H), 4.25 (t, 2H), 3.05 (t, 2H), 1.25(s, 6H); LCMS (m/z): 477.1 [C22H23BrN2O3S+H]⁺.

Step E{6-[3-Isopropoxy-5-(2-thiophen-3-yl-ethoxy)-benzoylamino]-pyridin-3-ylmethyl}-phosphonicacid diethyl ester

N-(5-Bromomethyl-pyridin-2-yl)-3-isopropoxy-5-(2-thiophen-3-yl-ethoxy)-benzamide(0.46 g. 0.97 mmol) was dissolved in DMF (5 mL). Triethyl phosphite(0.51 mL, 2.91 mmol) was added and the reaction mixture was subjected tomicrowave radiation at 180° C. for 30 minutes. The reaction mixture wasconcentrated under reduced pressure and partitioned in EtOAc (20 mL) andwater (20 mL). The organic layer was rinsed with water (10 mL), and thena saturated sodium chloride solution (10 mL), dried over sodium sulfate,filtered, and concentrated to dark brown oil. After chromatography onsilica gel with a gradient from 50-100% ethyl acetate-hexanes to 10%methanol-ethyl acetate,{6-[3-isopropoxy-5-(2-thiophen-3-yl-ethoxy)-benzoylamino]-pyridin-3-ylmethyl}-phosphonicacid diethyl ester (86.0 mg, 16.6% yield) was obtained. 1H NMR (300 MHz,DMSO-d₆): δ 10.85 (s, 1H), 8.25 (s, 1H), 8.10 (d, J=6.0 Hz, 1H), 7.70(d, J=6.0 Hz, 1H), 7.45 (d, J=3.0 Hz, 1H), 7.30 (s, 1H), 7.20 (s, 1H),7.15 (s, 1H), 7.10 (d, J=3.0 Hz, 1H), 6.65 (s, 1H), 4.70 (m, 1H), 4.25(t, 2H), 3.95 (m, 4H), 3.25 (d, J=12.0 Hz, 2H), 3.05 (t, 2H), 1.25 (s,6H), 1.15 (m, 6H); LCMS (m/z): 533.2 [C26H33N2O6PS+H]⁺.

Example 3{4-[3-Isopropoxy-5-(thiazol-2-ylcarbamoyl)-phenoxy]-phenyl}-phosphonicacid

Starting from{4-[3-isopropoxy-5-(thiazol-2-ylcarbamoyl)-phenoxy]-phenyl}-phosphonicacid diisopropyl ester (1.92 g, 3.78 mmol),{4-[3-isopropoxy-5-(thiazol-2-ylcarbamoyl)-phenoxy]-phenyl}-phosphonicacid was synthesized as a white solid (1.38 g, 3.11 mmol) according tothe TMSBr deprotection procedure in Example 1. 1H NMR (300 MHz,DMSO-d₆): δ 7.73-7.77 (m, 2H), 7.61 (m, 1H), 7.54 (s, 1H), 7.33-7.35 (m,2H), 7.13 (s, 1H), 7.12 (m, 1H), 6.87 (m, 1H), 4.77-4.82 (m, 1H), 1.35(d, J=6 Hz, 6H); LC-MS (m/z): 435.4 [C19H19N2O6PS+H]⁺. Anal. Calcd. for(C19H19N2O6PS+0.7H2O): C, 51.05; H, 4.60; N, 6.27. Found: C, 50.90; H,4.88; N, 6.67.

Intermediates for the preparation of Example 3 were prepared accordingto Route 3, as described below.

Route 3

Step A 3-Isopropoxy-5-(4-nitro-phenoxy)-benzoic acid methyl ester

To a solution of 3-hydroxy-5-isopropoxy-benzoic acid methyl ester (7.00g, 33.3 mmol) in acetone (80 mL) was added K₂CO₃ (5.06 g, 36.6 mmol) and1-fluoro-4-nitrobenzene (3.53 mL, 33.3 mmol) at rt. The resultingmixture was refluxed for 12 hr. Then the mixture was filtered through apad of Celite to remove insoluble salts and the cake was rinsed withacetone. Combined filtrates were concentrated under vacuum to afford aresidue which was purified by silica gel flash chromatography (7.5×30cm, hexane/EtOAc, v/v 10:1, 5:1). Fractions containing themono-alkylation product were pooled and concentrated to give3-isopropoxy-5-(4-nitro-phenoxy)-benzoic acid methyl ester (11.0 g, 44%)as a brown oil. ¹H NMR (300 MHz, CDCl₃): δ 8.22 (d, J=9 Hz, 2H), 7.43(dd, J=1, 2 Hz, 1H), 7.29 (dd, J=1, 2 Hz, 1H), 7.04 (d, J=9 Hz, 2H),6.80 (dd, J=2, 2 Hz, 1H), 4.56-4.64 (m, 1H), 3.90 (s, 3H), 1.35 (d, J=6Hz, 6H).

Step B 3-Isopropoxy-5-(4-nitro-phenoxy)-benzoic acid methyl ester

A mixture of 3-isopropoxy-5-(4-nitro-phenoxy)-benzoic acid methyl ester(11.0 g, 33.3 mmol) and Pd/C (3.50 g, 10% wt, 3.33 mmol) catalyst inEtOH/EtOAc (v/v 1:10, 44 mL) was hydrogenated using Parr apparatus at 50psi H₂ for 3 hr. The mixture was filtered through a pad of Celite andthe cake was washed with EtOAc. The combined filtrates wereconcentrated, azeotroped with toluene (1×) to give3-isopropoxy-5-(4-nitro-phenoxy)-benzoic acid methyl ester (8.94 g, 29.7mmol) as yellow oil. ¹H NMR (300 MHz, CDCl₃): δ 7.21 (dd, J=1, 2 Hz,1H), 7.13 (dd, J=1, 2 Hz, 1H), 6.86 (d, J=9 Hz, 2H), 6.68 (d, J=9 Hz,2H), 6.65 (dd, J=2, 2 Hz, 1H), 4.51-4.59 (m, 1H), 3.86 (s, 3H), 1.31 (d,J=6 Hz, 6H).

Step C 3-(4-Bromo-phenoxy)-5-isopropoxy-benzoic acid methyl ester

To a flask containing CuBr₂ (8.28 g, 37.1 mmol) in CH₃CN (100 mL) wasadded t-butyl nitrite (8.06 mL, 50.4 mmol) rt. The mixture was heated to65° C. Then a solution of 3-isopropoxy-5-(4-nitro-phenoxy)-benzoic acidmethyl ester in DMF (50 mL) was added slowly in 10 min. After theaddition was complete, the solution was left at 65° C. for 1 h. Cooledto rt. The mixture was concentrated and the residue was partitionedbetween HCl (1 N) and EtOAc. The organic layer was separated and washedwith brine (1×), dried and concentrated to give a residue, which waspurified by silica gel column (6×25 cm, hexane/EtOAc, v/v 10:1, 5:1).Fractions containing the product were pooled and concentrated to give3-(4-bromo-phenoxy)-5-isopropoxy-benzoic acid methyl ester as yellow oil(8.69 g, 71%). ¹H NMR (300 MHz, CDCl₃): δ 7.45 (d, J=9 Hz, 2H), 7.31(dd, J=1, 2 Hz, 1H), 7.19 (dd, J=1, 2 Hz, 1H), 6.90 (d, J=9 Hz, 2H),6.70 (dd, J=2, 2 Hz, 1H), 4.53-4.61 (m, 1H), 3.88 (s, 3H), 1.33 (d, J=6Hz, 6H).

Step D 3-[4-(Diisopropoxy-phosphoryl)-phenoxy]-5-isopropoxy-benzoic acidmethyl ester

To a stirred solution of 3-(4-bromo-phenoxy)-5-isopropoxy-benzoic acidmethyl ester (5.00 g) in toluene (120 mL) was added diisopropylphosphite (2.80 mL),dichloro[1,1′-bis(diphenylphosphino)-ferrocene]palladium (II)dichloromethane adduct (1.00 g, 1.37 mmol), triethylsilane (0.44 mL,2.74 mmol), and Et₃N (5.72 mL, 41.1 mmol) at rt. DCM (12 mL) was addedto the reaction flask which was purged with nitrogen. The mixture washeated at 90° C. overnight. Cooled to rt and concentrated. EtOAc andwater were added and the mixture was filtered through a pad of Celite toremove the insoluble. The organic layer was separated, washed with brine(1×), dried with anhydrous MgSO4, filtered, and concentrated. Theresidue was purified by silica gel column (6×25 cm, hexane/EtOAc,v/v=5:1, 1:1). Fractions containing the product were pooled andconcentrated to give3-[4-(Diisopropoxy-phosphoryl)-phenoxy]-5-isopropoxy-benzoic acid methylester (4.0 g, 65%) as yellow oil. ¹H NMR (300 MHz, CDCl₃): δ 7.77 (dd,J=9, 13 Hz, 2H), 7.36 (dd, J=1, 2 Hz, 1H), 7.26 (m, 1H), 7.02 (dd, J=4,9 Hz, 2H), 6.76 (dd, J=2, 2 Hz, 1H), 4.63-4.74 (m, 2H), 4.54-4.62 (m,1H), 1.37 (d, J=6 Hz, 6H), 1.33 (d, J=6 Hz, 6H) 1.24 (d, J=6 Hz, 6H).

Step E 3-[4-(Diisopropoxy-phosphoryl)-phenoxy]-5-isopropoxy-benzoic acid

Starting from3-[4-(Diisopropoxy-phosphoryl)-phenoxy]-5-isopropoxy-benzoic acid methylester (8.00 g, 17.8 mmol),3-[4-(diisopropoxy-phosphoryl)-phenoxy]-5-isopropoxy-benzoic acid wassynthesized as yellow oil (7.64 g, 17.6 mmol) according to Step C inExample 1. ¹H NMR (300 MHz, CDCl₃): δ 7.80 (dd, J=9, 13 Hz, 2H), 7.44(dd, J=1, 2 Hz, 1H), 7.33 (dd, J=1, 2 Hz, 1H), 7.05 (dd, J=4, 9 Hz, 2H),6.81 (dd, J=2, 2 Hz, 1H), 4.67-4.78 (m, 2H), 4.56-4.64 (m, 1H), 1.39 (d,J=6 Hz, 6H), 1.35 (d, J=6 Hz, 6H) 1.25 (d, J=6 Hz, 6H).

Step F{4-[3-isopropoxy-5-(thiazol-2-ylcarbamoyl)-phenoxy]-phenyl}-phosphonicacid diisopropyl ester

Starting from3-[4-(diisopropoxy-phosphoryl)-phenoxy]-5-isopropoxy-benzoic acid (7.64g, 17.6 mmol) and 2-aminothiazole (1.84 g, 18.4 mmol),{4-[3-isopropoxy-5-(thiazol-2-ylcarbamoyl)-phenoxy]-phenyl}-phosphonicacid was synthesized as yellow gum (8.80 g, 17.0 mmol) according to StepD in Example 1. ¹H NMR (300 MHz, CDCl₃): δ 7.78 (dd, J=9, 13 Hz, 2H),7.29-7.30 (m, 1H), 7.18-7.20 (m, 2H), 7.04 (dd, J=4, 9 Hz, 2H), 6.94 (dJ=4 Hz, 1H), 6.78 (dd, J=2, 2 Hz, 1H), 4.63-4.74 (m, 2H), 4.51-4.59 (m,1H), 1.36 (d, J=6 Hz, 6H), 1.33 (d, J=6 Hz, 6H) 1.24 (d, J=6 Hz, 6H).

Example 4{4-[3-Isobutyl-5-(thiazol-2-ylcarbamoyl)phenoxy]phenyl}phosphonic acid

The title compound was prepared from 3-hydroxy-5-isobutylbenzoic acidmethyl ester in the same manner as described in Example 3 withmodifications evident to an individual skilled in the art. ¹H NMR (500MHz, DMSO-d₆) δ 0.89 (d, 6H, J=7 Hz), 1.92 (m, 1H), 2.54 (d, 2H, J=7Hz), 7.10 (dd, 1H, J=8, 3 Hz), 7.17 (s, 1H), 7.28 (d, 1H, J=3 Hz), 7.55(d, 1H, J=3 Hz), 7.58 (t, 1H, J=2 Hz), 7.70 (dd, 2H, J=12, 8 Hz), 7.79(s, 1H); LCMS m/z=433.1 [C₂₀H₂₁N₂O₅PS+H]⁺.

Step A 3-Benzyloxy-5-hydroxy-benzoic acid methyl ester

To a solution of methyl 3,5-dihydroxybenzoate (15.0 g, 89.21 mmol) in350 mL of acetone was added potassium carbonate (13.56 g, 98.13 mmol)followed by benzyl bromide (11.2 mL, 93.6 mmol). And the mixturerefluxed for 3 h. After cooling to rt the solids were filtered and thefiltrate was evaporated. The residue was chromatographed on silica gelusing an EtOAc-hexane gradient to afford 7.08 g (31%) of3-benzyloxy-5-hydroxybenzoic acid methyl ester. ¹H NMR (300 MHz,DMSO-d₆) δ 3.81 (s, 3H), 5.10 (s, 2H), 6.64-6.66 (m, 1H), 6.97-7.01 (m,2H), 7.35-7.45 (m, 5H), 9.89 (br s. 1H).

Step B 3-Benzyloxy-5-trifluoromethanesulfonyloxybenzoic acid methylester

To a solution of 3-benzyloxy-5-hydroxybenzoic acid methyl ester (1.50 g,5.81 mmol) in DCM (60 mL) at −78° C. was added diisopropylethylamine(1.05 mL, 6.39 mmol). After stirring at −78° C. for 20 min,trifluoromethanesulfonic anhydride (1.07 mL, 6.39 mmol) was added andthe mixture stirred at room temperature for 30 min. The reaction mixturewas diluted with 150 ml of diethyl ether and the organic layer washedwith 1N HCl, brine, dried (MgSO₄) and evaporated to afford 2.28 g (100%)of 3-Benzyloxy-5-trifluoromethanesulfonyloxybenzoic acid methyl ester.¹H NMR (500 MHz, DMSO-d₆) δ 3.87 (s, 3H), 5.25 (s, 2H), 7.35-7.37 (m,1H), 7.39-7.41 (m, 2H), 7.47-7.49 (m, 2H), 7.52-7.56 (m, 2H), 7.65-7.66(m, 1H).

Step C 3-Benzyloxy-5-isobutylbenzoic acid methyl ester

To a microwave reaction vial was added3-benzyloxy-5-trifluoromethanesulfonyloxybenzoic acid methyl ester (70mg, 0.179 mmol), lithium chloride (23 mg. 0.537 mmol), Pd(PPh₃)₄ (10 mg,0.009 mmol) and 3 ml of THF. Isobutylzinc bromide (0.5 M in THF) (0.537mL, 0.269 mmol) was added and the vial sealed. After heating inmicrowave reactor at 1300 for 5 min the reaction mixture was adsorbedonto silica gel and purified by silica gel chromatography using an ethylacetate-hexane gradient to afford 36 mg (68%) of3-benzyloxy-5-isobutylbenzoic acid methyl ester. ¹H NMR (300 MHz.DMSO-d₆) δ 0.850 (d, 6H, J=6 Hz), 1.78-1.92 (m, 1H), 3.84 (s, 3H), 5.16(s, 2H), 7.11 (d, 1H, J=2 Hz), 7.33-7.48 (m, 7H).

Step D 3-Hydroxy-5-isobutylbenzoic acid methyl ester

To a solution of 3-benzyloxy-5-isobutylbenzoic acid methyl ester (388mg. 1.30 mmol) in ethanol (20 mL) was added palladium hydroxide (80 mg,20 wt % on carbon). After shaking on Parr hydrogenation apparatus for 3h at 45 psi, the catalyst was filtered through a pad of Celite and thesolvent evaporated to afford 271 mg (100%) of3-hydroxy-5-isobutylbenzoic acid methyl ester. ¹H NMR (300 MHz, DMSO-d₆)δ 0.850 (d, 6H, J=6 Hz), 1.77-1.84 (m, 1H), 2.42 (d, 2H, J=7 Hz), 3.81(s, 3H), 6.81-6.82 (m, 1H), 7.17-7.19 (m, 2H), 9.70 (s, 1H).

Example 5{4-[3-(5-Chlorothiazol-2-ylcarbamoyl)-5-cyclopentyloxyphenoxy]phenyl}phosphonicacid

The title compound was prepared from 3-(4-bromophenoxy)-5-hydroxybenzoicacid methyl ester in a similar manner to Example 3 with modificationsevident to an individual skilled in the art. ¹H NMR (500 MHz, DMSO-d₆) δ1.58-1.61 (m, 2H), 1.69-1.74 (m, 4H), 1.91-1.96 (m, 2H), 4.94 (m, 1H),6.87 (t, 1H, J=2 Hz). 7.13 (dd, 2H, J=9, 2 Hz), 7.28 (t, 1H, J=2 Hz),7.48 (t, 1H, J=2 Hz), 7.61 (s, 1H), 7.71 (dd, 2H, J=12, 9 Hz); LCMSm/z=495.4 [C₂₁H₂₀ClN₂O₆PS+H]⁺; Anal. Calcd. for C₂₁H₂₀ClN₂O₆PS: C,50.97; H, 4.07; N, 5.66. Found: C, 50.61; H, 3.70; N, 5.54.

Step A 3-(4-Bromo-phenoxy)-5-hydroxybenzoic acid methyl ester

To a solution of methyl 3,5-dihydroxybenzoate (8.0 g, 47.6 mmol) in DCM(800 mL) was added 4-bromophenylboronic acid (9.56 g, 47.6 mmol),copper(II)acetate (8.6 g, 47.6 mmol), 4 A molecular sieves (4 g), andpyridine (19.4 mL, 238.0 mmol). After stirring at rt for 72 h, more4-bromophenylboronic acid (7 g, 35 mmol) was added and stirringcontinued for another 16 h. The solvent was evaporated and the reactionmixture was re-dissolved in diethyl ether. Washed with 1N HCl, brine,dried (MgSO₄) and evaporated. The residue was subjected to silica gelchromatography using an ethyl acetate-hexane gradient to afford 3.4 g(22%) of 3-(4-Bromophenoxy)-5-hydroxybenzoic acid methyl ester. ¹H NMR(300 MHz, DMSO-d₆) δ 3.78 (s, 3H), 6.64-6.66 (m, 1H), 6.89 (dd, 1H, J=2,1 Hz), 7.02 (dd, 2H, J=7, 2 Hz), 7.12 (dd, 1H, J=2, 1 Hz), 7.57 (dd, 2H,J=7, 2 Hz).

Example 6{6-[3-Isopropoxy-5-(4-methanesulfonyl-phenoxy)-benzoylamino]-pyridin-3-yl}-methyl-phosphinicacid

The title compound was prepared from3-isopropoxy-5-(4-methanesulfonyl-phenoxy)-benzoic acid methyl ester ina similar manner to Example 1 with modifications evident to anindividual skilled in the art. ¹H NMR (500 MHz, DMSO-d₆) δ 10.99 (br,1H), 8.58 (m, 1H), 8.12 (m, 1H), 8.02 (m, 1H), 7.91 (d, J=9 Hz, 2H),7.47 (m, 1H), 7.30 (m, 1H), 7.21 (d, J=9 Hz, 2H), 6.90 (m, 1H),4.72-4.79 (m, 1H), 3.18 (s, 3H), 1.27 (d, J=6 Hz, 6H). LC-MS (m/z):507.4 [C22H23N2O8PS+H]⁺. Anal. Calcd. for (C22H23N2O8PS+0.5 HBr): C,47.38; H, 4.67; N, 5.53. Found: C, 47.65; H, 4.47; N, 5.28.

Step A 3-Isopropoxy-5-(4-methanesulfonyl-phenoxy)-benzoic acid methylester

To a solution of 3-hydroxy-5-isopropoxy-benzoic acid methyl ester (3.20g, 15.2 mmol) in DMF (80 mL) was added Cs₂CO₃ (5.45 g, 16.7 mmol) and4-fluorophenyl methyl sulfone (2.65 g, 15.2 mmol) at rt. The resultingmixture was heated at 115° C. for 12 hr. Then the mixture wasconcentrated. The resulting residue was partitioned between EtOAc andwater. The aqueous layer was separated and extracted with EtOAc (2×).Combined organic layers were washed with water (1×), dried andconcentrated to a residue, which was purified by silica gel flashchromatography (7.5×30 cm, hexane/EtOAc, v/v 5:1, 2:1, 1:1). Fractionscontaining the mono-alkylation product were pooled and concentrated togive 3-isopropoxy-5-(4-methanesulfonyl-phenoxy)-benzoic acid methylester (5.60 g, 100%) as a yellow oil. ¹H NMR (300 MHz, CDCl₃): δ 8.90(d, J=9 Hz, 2H), 7.41 (m, 1H), 7.26 (m, 1H), 7.10 (d, J=9 Hz, 2H), 6.79(m, 1H), 4.56-4.63 (m, 1H), 3.90 (s, 3H), 3.06 (s, 3H), 1.35 (d, J=6 Hz,6H).

Example 7{6-[(2-Isobutoxy-6-isopropoxy-pyridine-4-carbonyl)-amino]-pyridin-3-yl}-phosphonicacid

The title compound was prepared from2-isobutoxy-6-isopropoxyisonicotinic acid in a similar manner to Example1 with modifications evident to an individual skilled in the art. ¹H NMR(300 MHz, DMSO-d₆) δ 0.98 (d, 6H, J=7 Hz), 1.32 (d, 6H, J=6 Hz),2.00-2.09 (m, 1H), 4.05 (d, 2H, J=6 Hz), 5.13-5.22 (m, 1H), 6.79 (d, 1H,J=1 Hz), 6.86 (d, 1H, J=1 Hz), 8.02-8.09 (m, 1H), 8.20-8.24 (m, 1H),8.57-8.61 (m, 1H), 11.10 (s, 1H). LCMS m/z 410.4 [C₁₈H₂₄N₃O₆P+H]⁺. Anal.Calcd. for C₁₈H₂₄N₃O₆P+0.7H₂O: C, 51.23; H, 6.07; N, 9.96. Found: C,51.26; H, 6.00; N. 9.86.

Step A 2-Chloro-6-isopropoxyisonicotinic acid

To a solution of 2,6-dichloroisonicotinic acid (1.26 g, 6.56 mmol) inisopropanol (20 mL) was added 27 mL (16.40 mmol) of freshly made sodiumisopropoxide (0.61 M in isopropanol). This mixture was split evenly intofour 20 mL microwave vials and each vial was heated under microwaveirradiation at 150° C. for 10 min. The combined reaction solutions wereeluted through a column of Dianion HP-20 PS resin eluting first withwater followed by 100% acetonitrile to provide 770 mg (54%) of2-chloro-6-isopropoxyisonicotinic acid. ¹H NMR (300 MHz, DMSO-d₆) δ 1.27(d, 6H, J=6 Hz), 5.08-5.14 (m, 1H), 6.95 (s, 1H), 7.23 (s, 1H)

Step B 2,6-Diisopropoxy-isonicotinic acid

To a flask containing 2-chloro-6-isopropoxyisonicotinic acid (1.05 g,4.83 mmol) was added 28 mL (9.66 mmol) of freshly prepared sodiumisobutoxide (0.35 M in isobutanol). This mixture was split evenly intotwo 20 mL microwave vials and each vial was heated under microwaveirradiation at 210° C. for 20 min. The reaction mixture was purified byC18 medium pressure chromatography using a gradient of acetonitrile inwater to afford 310 mg (25%) of 2-isobutoxy-6-isopropoxyisonicotinicacid. ¹H NMR (300 MHz, DMSO-d₆) δ 0.95 (d, 6H, J=7 Hz), 1.27 (d, 6H, J=6Hz), 1.96-2.05 (m, 1H), 3.96 (d, 2H, J=7 Hz), 5.05-5.13 (m, 1H), 6.59(s, 1H), 6.63 (s, 1H).

Example 8{4-[5-(Thiazol-2-ylcarbamoyl)-biphenyl-3-yloxy]-phenyl}-phosphonic acid

The title compound was prepared from 5-benzyloxybiphenyl-3-carboxylicacid methyl ester in a similar manner to Example 4 with modificationsevident to an individual skilled in the art. ¹H NMR (300 MHz, DMSO-d₆) δ7.02-7.04 (m, 2H), 7.14 (d, 1H, J=3 Hz), 7.26-7.29 (m, 1H), 7.34-7.37(m, 2H), 7.42 (d, 1H, J=3 Hz), 7.49-7.59 (m, 4H), 7.67-7.69 (m, 2H),8.16 (t, 1H, J=2 Hz); LCMS m/z=453.4 [C₂₂H₁₇N₂O₅PS+H]⁺. Anal. Calcd. forC₂₂H₁₇N₂O₅PS: C, 58.41; H, 3.79; N, 6.19. Found: C, 58.24, H, 3.78; N,5.99.

Step A 5-Benzyloxybiphenyl-3-carboxylic acid methyl ester

To a mixture of THF/H₂O (S mL, v/v=4:1) in a microwave vial was added3-benzyloxy-5-trifluoromethanesulfonyloxy-benzoic acid methyl ester (100mg, 0.256 mmol), phenylboronic acid (34 mg, 0.281 mmol), potassiumcarbonate (71 mg, 0.512 mmol), and Pd(PPh₃)₄ (15 mg, 0.02 mmol). Thereaction vessel was sealed and subjected to microwave heating for 5 minat 130° C. After cooling, it was diluted with diethyl ether and washedwith brine, dried (MgSO₄), and evaporated. The residue was subjected tochromatography on silica gel using an ethyl acetate-hexane gradient toafford 74 mg (90%) of 5-benzyloxybiphenyl-3-carboxylic acid methylester: LCMS m/z=319.4 [C₂₁H₁₈O₃+H]⁺.

Example 9{4-[3-(4-Chloro-thiazol-2-ylcarbamoyl)-5-(3,5-dimethyl-isoxazol-4-yl)-phenoxy]-phenyl}-phosphonicacid

The title compound was prepared from3-benzyloxy-5-trifluoromethanesulfonyloxy-benzoic acid methyl ester in asimilar manner to Example 8 with modifications evident to an individualskilled in the art. ¹H NMR (500 MHz, DMSO-d₆) δ 2.27 (s, 3H), 2.46 (s,3H), 7.18 (dd, 2H, J=9, 3 Hz), 7.45 (dd, 1H, J=2, 2 Hz), 7.62 (s, 1H),7.71-7.75 (m, 3H), 7.91 (t, 1H, J=2 Hz); LCMS m/z=506.1[C₂₁H₁₇ClN₃O₆PS+H]⁺. Anal. Calcd. for (C₂₁H₁₇ClN₃O₆PS+0.75 HBr): C,44.52: H. 3.16; N, 7.42. Found: C, 44.61; H, 3.28; N, 7.15.

Example 10{4-[3-(5-Chloro-thiazol-2-ylcarbamoyl)-5-phenoxy-phenoxy]-phenyl}-phosphonicacid

The title compound was prepared from3-(4-bromo-phenoxy)-5-hydroxybenzoic acid methyl ester in a similarmanner to Example 3 with modifications evident to an individual skilledin the art. ¹H NMR (500 MHz, DMSO-d₆) δ 7.02 (t, 1H, J=2 Hz), 7.14-7.25(m, 5H), 7.44-7.52 (m, 4H), 7.60 (s, 1H), 7.70-7.74 (m, 2H). LCMSm/z=503.4 [C₂₂H₁₆ClN₂O₆PS+H]⁺; Anal. Calcd. for C₂₂H₁₆ClN₂O₆PS: C,52.55; H, 3.21; N, 5.57. Found: C, 52.37; H, 3.08; N, 5.29.

Step A 3-(4-Bromophenoxy)-5-phenoxybenzoic acid methyl ester

To a solution of 3-(4-bromophenoxy)-5-hydroxybenzoic acid methyl ester(200 mg, 0.619 mmol) in 10 mL of acetonitrile was added iodobenzene (189mg, 0.928 mmol), cesium carbonate (403 mg, 1.24 mmol), copper(I)oxide (5mg, 0.03 mmol), magnesium sulfate (185 mg), and dimethylglyoxime (14 mg,0.124 mmol). The mixture was stirred at reflux for 16 h. Then themixture was filtered through a pad of Celite and the filtrate wasevaporated. The residue was chromatographied on silica gel using anethyl acetate-hexane gradient afforded 58 mg (23%) of3-(4-bromophenoxy)-5-phenoxybenzoic acid methyl ester: ¹H NMR (300 MHz,DMSO-d₆) δ 3.79 (s, 3-1), 7.00-7.02 (m, 1H), 7.08-7.18 (m, 6H),7.20-7.26 (m, 1H), 7.43-7.46 (m, 2H), 7.61 (d, 2H, J=9 Hz).

Example 11{5-[3-Isopropoxy-5-(thiazol-2-ylcarbamoyl)-benzyl]-thiophen-2-yl}-phosphonicacid

The title compound was prepared from3-[5-(diethoxy-phosphoryl)-thiophen-2-ylmethyl]-5-isopropoxy-benzoicacid in a similar manner to Example 3 with modifications evident to anindividual skilled in the art. ¹H NMR (300 MHz, DMSO-d₆): δ 7.57 (m,3H), 7.28 (m, 2H), 7.07 (m, 1H), 7.00 (m, 1H), 4.74 (m, 1H), 4.21 (m,2H), 1.31 (m, 6H). LC-MS m/z=439.4 [C18H19N2O5PS2+H]⁺; Anal Calcd for(C18H19N2O5PS2+0.15 HBr): C, 47.98 H, 4.28; N, 6.22. Found: C, 47.95; H,4.29; N, 5.98.

Intermediates for the preparation of Example 11 were prepared accordingto Route 4, as described below.

Route 4

Step A 3-Bromo-5-isopropoxy-benzonitrile

To a solution of IM NaHMDS (74.26 ml, 74.26 mmol) in DMF was added2-propanal (5.69 ml, 74.26 mmol) at r.t. After stirring for 5 min3-bromo-5-fluoro-benzonitrile was added. The reaction mixture wasstirred at r.t. for 2 hrs, concentrated down. The residue was thenpartitioned between EtOAc and water. The organic layer was collected andthe water layer was back-extracted with EtOAc once. The combined organiclayers were dried over MgSO₄, filtrated, concentrated, purified byBiotage (5% EtOAc) to afford the final product3-bromo-5-isopropoxy-benzonitrile (9.46 g, 79.0%). ¹H NMR (300 MHz,DMSO-d₆): δ 7.62 (m, 1H), 7.47 (m, 1H), 7.44 (m, 1H), 4.73 (m, 2H), 1.24(d, J=6.3 Hz, 6H). LC-MS m/z=241.4 [C10H10BrNO+H]⁺.

Step B 3-Bromo-5-isopropoxy-benzoic acid

To a solution of 3-bromo-5-isopropoxy-benzonitrile (6.0 g, 24.78 mmol)in EtOH (80 ml) was added water (8.0 ml), followed by 50% NaOH (6.52 ml,123.91 mmol). The reaction mixture was then refluxed for 2 hrs,concentrated down, re-dissolved in water, acidified with HCl, extractedwith EtOAc. The EtOAc layer was separated, dried over MgSO₄, filtrated,and concentrated to afford the final product3-bromo-5-isopropoxy-benzoic acid (6.36 g, 100%). ¹H NMR (300 MHz,DMSO-d₆): δ 13.31 (s, 1H), 7.56 (s, 1H), 7.36 (m, 2H), 4.70 (m, 2H),1.25 (d, J=6.0 Hz, 6H). LC-MS m/z=260.4 [C10H11BrO3+H]⁺.

Step C 1, 3-Dimethyl-2-thiophen-2-yl-imidazolidine

To a solution of 2-thiophenecarboxaldehyde (8.6 ml, 104 mmol) in toluenewas added N,N′-dimethylethylene amine (11.0 ml, 104 mmol) at 0° C. Thereaction mixture was heated to reflux after the addition was complete.After 3 h at reflux, the mixture was cooled to rt, concentrated down toafford the final product 1, 3-dimethyl-2-thiophen-2-yl-imidazolidine (20g, 100%). ¹H NMR (300 MHz, DMSO-d₆): δ 7.47 (d, J=5.4 Hz, 1H), 7.09 (d,J=3.3 Hz, 1H), 6.94 (m, 1H), 3.60 (s, 1H), 3.18 (m, 4H), 2.11 (s, 6H).

Step D [5-(1, 3-Dimethyl-imidazolidin-2-yl)-thiophen-2-yl]-phosphonicacid diethyl ester

To a solution of 1,3-Dimethyl-2-thiophen-2-yl-imidazolidine (10 g, 60.17mmol) in THF was added TMEDA (9.1 ml, 60.17 mmol), cooled to −78° C.,then added 1.6 M nBuLi (47 m, 75.21 mmol). After stirring at −78° C. for30 min the mixture was warmed up to 0° C. in 1 hr and treated withdiethyl chlorophosphonate (10.4 ml, 72.2 mmol). The reaction mixture wasstirred at 0° C. for another 30 min. The reaction was then quenched byadding EtOAc and water. The EtOAc layer was separated and the waterlayer was further extracted with EtOAc once. The combined EtOAc layerswere dried over MgSO₄, filtrated and concentrated to afford the crudeproduct [5-(1, 3-dimethyl-imidazolidin-2-yl)-thiophen-2-yl]-phosphonicacid diethyl ester (17 g). ¹H NMR (300 MHz, DMSO-d₆): δ 7.44 (m, 1H),7.24 (m, 1H), 4.01 (m, 4H), 3.18 (m, 2H), 2.53 (m, 2H), 1.22 (m, 9H).

Step E (5-Formyl-thiophen-2-yl)-phosphonic acid diethyl ester

To a solution of [5-(1,3-dimethyl-imidazolidin-2-yl)-thiophen-2-yl]-phosphonic acid diethylester (17.2 g, 60.17 mmol) in water (20 ml) was added sulfuric acid (3ml) over 5 mins. The reaction was stirred at r.t. for 20 min, dilutedwith water, extracted with EtOAc. The organic layer was washed with sat.NaHCO₃, dried over MgSO₄, filtrated, concentrated, purified by Biotage(80% EtOAc) to give (5-formyl-thiophen-2-yl)-phosphonic acid diethylester (7.2 g, 48.3%). ¹H NMR (300 MHz, DMSO-d₆): δ 10.02 (d, J=2.4 Hz,1H), 8.09 (m, 1H), 7.75 (m, 1H), 4.05 (m, 4H1), 1.24 (m, 6H). LC-MSm/z=249.4 [C9H13O4PS+H]⁺.

Step F3-{[5-(Diethoxy-phosphoryl)-thiophen-2-yl]-hydroxy-methyl}-5-isopropoxy-benzoicacid

To a solution of 3-bromo-5-isopropoxy-benzoic acid (2.0 g, 8.26 mmol) inTHF (30 ml) was added 1.6 M nBuLi (10.6 mL 16.94 mmol) at −78° C. Thereaction was stirred at −78° C. for 1 h and treated with a solution of(5-formyl-thiophen-2-yl)-phosphonic acid diethyl ester (2.5 g. 9.91mmol) in THF. After stirring at −78° C. for 30 min, the reaction mixturewas warmed up to r.t. and quenched by water, diluted with EtOAc. Theaqueous layer was separated, acidified with 2N HCl to pH<1, andextracted with EtOAc (3×). The combined EtOAc layers were dried overMgSO₄, filtrated, concentrated to give the crude product3-{[5-(diethoxy-phosphoryl)-thiophen-2-yl]-hydroxy-methyl}-5-isopropoxy-benzoicacid.

Step G3-[5-(Diethoxy-phosphoryl)-thiophen-2-ylmethyl]-5-isopropoxy-benzoicacid

To a solution of3-{[5-(diethoxy-phosphoryl)-thiophen-2-yl]-hydroxy-methyl}-5-isopropoxy-benzoicacid (700 m g, 1.64 mmol) in CH₂Cl₂ (10 ml) was added TFA (1.1 ml),followed by triethylsilane (0.92 ml, 5.72 mmol). The reaction mixturewas then stirred at r.t. for 30 min, concentrated down, re-dissolved inwater, extracted with EtOAc. The EtOAc layer was separated, dried overMgSO₄, filtrated, and concentrated to afford the crude product3-[5-(diethoxy-phosphoryl)-thiophen-2-ylmethyl]-5-isopropoxy-benzoicacid.

Example 12{4-[2-(5-Chloro-thiazol-2-ylcarbamoyl)-quinolin-4-yloxy]-phenyl}-phosphonicacid

The title compound was prepared from 4-chloro-quinoline-2-carboxylicacid ethyl ester in a similar manner to Example 3 with modificationsevident to an individual skilled in the art. ¹H NMR (300 MHz, DMSO-d₆):δ 8.48 (d, J=8.1 Hz), 8.36 (d, J=8.7 Hz), 8.08 (m, 1H), 7.94 (m, 3H),7.72 (s, 1H), 7.54 (m, 2H), 7.32 (s, 1H). LC-MS m/z=462.4[C19H13ClN3O5PS+H]⁺; Anal Calcd for (C19H13ClN3O5PS+0.8H2O): C, 47.92 H,3.09; N, 8.82. Found: C, 47.77; H, 3.12; N, 9.10.

Step A 4-(4-Bromo-phenoxy)-quinoline-2-carboxylic acid ethyl ester

To a solution of 4-chloro-quinoline-2-carboxylic acid ethyl ester (910mg, 3.87 mmol) in DMF (15 ml) was added 4-bromophenol (737 mg, 4.26mmol), followed by Cs₂CO₃ (1.89 g, 5.81 mmol). The reaction mixture wasthen heated to 60° C. for 16 hrs. On the second day the mixture wascooled to r.t. and concentrated down. The residue was partitionedbetween EtOAc (10 ml) and water (20 ml). The EtOAc layer was separated,dried over MgSO₄, filtrated, concentrated, and purified by Biotage withEtOAc/Hexane (15%, 4 CV) to afford4-(4-bromo-phenoxy)-quinoline-2-carboxylic acid ethyl ester (609 mg,42.3%). ¹H NMR (300 MHz, DMSO-d₆): δ 8.36 (m, 1H), 8.18 (m, 1H), 7.93(m, 1H), 7.80 (m, 1H), 7.75 (m, 2H), 7.34 (m, 2H), 7.14 (s, 1H), 4.34(m, 2H), 1.30 (m, 3H). LC-MS m/z=373 [C18H14BrNO3+H]⁺.

Example 13{4-[2-(5-Fluoro-thiazol-2-ylcarbamoyl)-quinolin-4-yloxy]-phenyl}-phosphonicacid

The title compound was prepared from 4-Chloro-quinoline-2-carboxylicacid ethyl ester in a similar manner to Example 12 with modificationsevident to an individual skilled in the art. ¹H NMR (300 MHz, DMSO-d₆):δ 8.35 (d, J=7.8 Hz), 8.23 (d, J=7.8 Hz), 7.96 (m, 1H), 7.82 (m, 3H),7.41 (m, 3H), 7.19 (s, 1H). LC-MS m/z=446.4 [C19H13FN3O5PS+H]⁺; AnalCalcd for (C19H13FN3O5PS+0.1 HBr+0.5H2O): C, 49.35 H, 3.07; N, 9.09.Found: C, 49.07; H, 3.27; N, 9.49.

Example 14(5-{2-[3-Isopropoxy-5-(4-methanesulfonyl-phenoxy)-benzoylamino]-thiazol-4-yl}-thiophen-2-yl)-phosphonicacid

The title compound was prepared from[5-(2-amino-thiazol-5-yl)-thiophen-2-yl]-phosphonic acid diethyl esterin a similar manner to Example 6 with modifications evident to anindividual skilled in the art. ¹H NMR (300 MHz, DMSO-d₆): δ 12.93 (s,1H), 8.02 (m, 2H), 7.75 (s, 1H), 7.66 (m, 2H), 7.47 (m, 2H), 7.33 (m,2H), 7.06 (m, 1H), 4.86 (m, 1H), 3.29 (s, 3H), 1.38 (d, J=6.3 Hz, 6H).LC-MS m/z=625.6 [C24H23N2O8PS3+H]⁺; Anal Calcd for (C24H23N2O8PS3+0.2HBr): C, 47.19 H, 3.83; N, 4.59. Found: C, 47.40; H, 3.91; N, 4.26.

Step A (5-Acetyl-thiophen-2-yl)-phosphonic acid diethyl ester

(5-Acetyl-thiophen-2-yl)-phosphonic acid diethyl ester was madeaccording to Mu, X. J.; Zou. J. P.; Qian, Q. F.; Zhang, W. Org. Lett.,2006, 8, 5291-5293: ¹H NMR (300 MHz, DMSO-d₆): δ 7.99 (m, 1H), 7.68 (m,1H), 4.06 (m, 4H), 1.24 (m, 6H).

Step B [5-(2-Amino-thiazol-5-yl)-thiophen-2-yl]-phosphonic acid diethylester

To a solution of (5-acetyl-thiophen-2-yl)-phosphonic acid diethyl ester(1.13 g, 4.31 mmol) in EtOH (80 ml) was added CuBr₂ (959 mg, 8.62 mmol).The reaction mixture was then refluxed for 3 hr, diluted with EtOAc,quenched by adding sat. NaHCO₃. After layers were separated, the org,layer was collected and the aqueous layer was further extracted withEtOAc once. Combined organic layers were dried over MgSO₄, filtrated,and concentrated. The residue was then dissolved in EtOH/EtOAc (4 ml/16ml) and treated with thiourea (394 mg, 5.17 mmol). The reaction mixturewas then heated to reflux for 1 hr, cooled to r.t., and concentrateddown. The residue was partitioned between EtOAc and water. The organiclayer was collected, dried over MgSO₄, filtrated, concentrated, andpurified by Biotage to give the final compound (218 mg, 15.9%). ¹H NMR(300 MHz, DMSO-d₆): δ 7.50 (m, 2H), 7.23 (s, 2H), 7.10 (s, 1H), 4.02 (m,4H), 1.21 (m, 6H). LC-MS m/z=263.4 [C7H7N2O3PS2+H]⁺.

Example 15{6-[2-Amino-4-fluoro-5-(1-methyl-1H-imidazol-2-ylsulfanyl)-benzoylamino]-pyridin-3-yl}-methyl-phosphinicacid hydroiodide salt

In a similar manner to Example 1, a mixture of isopropyl2-amino-N-(5-bromo-pyridin-2-yl)-4-fluoro-5-(1-methyl-1H-imidazol-2-ylsulfanyl)-benzamide(57 mg, 0.12 mmol) and iodotrimethylsilane (0.07 mL, 0.49 mmol) in 2 mLof CH₂Cl₂ was stirred for 90 min at rt and the solvents evaporated. Theresidue was sonicated in 1 mL of CH₃CN, the solvent evaporated, theresidue sonicated in 1 mL CH₃CN and 0.1 mL water, the solvent evaporatedand the residue suspended in CH₃CN and the resulting solid collected byfiltration. It was dissolved in 1:1 CH₃CN/water and subjected to MPLCpurification through a 25 g C18 column eluting with % acetonitrile inwater (time): 10 (3 min), 15 (15 min). Lyophilization of the eluentcontaining the desired product provided 31 mg (46%) of the titlecompound as an amorphous solid: ¹H NMR (500 MHz, DMSO-d₆): δ 1.57 (d,3H, J=15 Hz), 3.79 (s, 3H), 6.64 (d, 1H, J=12 Hz), 7.15 (br s. 2H), 7.37(br s, 1H), 7.57 (s, 1H), 8.11 (ddd, 1H, J=10, 8, 2 Hz), 8.16 (d, 1H,J=8 Hz), 8.17 (dd, 1H, J=8, 2 Hz), 8.65 (dq, 1H, J=6, 1 Hz); LCMS (m/z):422.1 [C₁₇H₁₇FN₅O₃PS+H]⁺. Anal. calcd. for (C₁₇H₁₇FN₅O₃PS+HI+H₂O): C,36.06; H, 3.38; N, 12.37. Found: C, 36.22; H, 3.39; N, 12.18.

Intermediates for the preparation of Example 15 were prepared accordingto Route 5, as described below.

Route 5

Step A N-(5-Bromo-pyridin-2-yl)-4,5-difluoro-2-nitro-benzamide

Conducted as described for Step D of Example 1 using4,4-difluoro-2-nitrobenzoic acid (2500 mg, 12.3 mmol) and2-amino-5-bromopyridine (2340 mg, 13.5 mmol) and substitutingdichloroethane for CH₂Cl₂ in the acid chloride forming step. The solidresidue obtained after extractive isolation was recrystallized fromEtOAc to provide 2.43 g of the title compound. A second crop from thefiltrate provided a further 549 mg to make a total of 2.98 g (68%) ofthe title compound as a yellow crystalline solid. ¹H NMR (500 MHz,DMSO-d₆): δ 8.07 (dd, 1H, J=10, 8 Hz), 8.11 (dd, 1H, J=9, 2 Hz), 8.14(d, 1H, J=9 Hz), 8.46 (dd, 1H, J=10, 7 Hz), 8.50 (br s, 1H), 11.45 (s,1H); LCMS (m/z): 358/360 [C₁₂H₆BrF₂N₃O₃+H]⁺.

Step BN-(5-Bromo-pyridin-2-yl)-4-fluoro-5-(1-methyl-1H-imidazol-2-ylsulfanyl)-2-nitro-benzamide

A mixture of N-(5-bromo-pyridin-2-yl)-4,5-difluoro-2-nitro-benzamide(236 mg, 0.66 mmol), 2-mercapto-1-methylimidazole (83 mg, 0.73 mmol) andtriethylamine (0.18 mL, 1.32 mmol) in 2 mL CH₃CN was microwave heated to130° C. for 10 min and the resulting solid was collected by filtration,rinsed with CH₃CN, and dried under high vacuum to provide 214 mg (72%)of the title compound as a yellow solid. ¹H NMR (500 MHz, DMSO-d₆): δ3.70 (s, 3H), 6.91 (d, 1H, J=7 Hz), 7.20 (d, 1H, J=1 Hz), 7.58 (d, 1H,J=1 Hz), 8.07 (br s, 2H), 8.24 (d, 1H, J=10 Hz), 8.47 (br s, 1H), 11.39(s, 1H); LCMS (m/z): 452/454 [C₁₆H₁₁BrFN₅O₃S+H]⁺.

Step C2-Amino-N-(5-bromo-pyridin-2-yl)-4-fluoro-5-(1-methyl-1H-imidazol-2-ylsulfanyl)-benzamide

A mixture ofN-(5-bromo-pyridin-2-yl)-4-fluoro-5-(1-methyl-1H-imidazol-2-ylsulfanyl)-2-nitro-benzamide(1.42 g, 3.14 mmol), 325 mesh iron dust (7.1 g, 127 mmol), 6 mL of 4 Maqueous NH₄Cl and 60 mL of isopropanol were mechanically stirred at 85°C. for 4 h, then slurried hot with Celite and filtered. The filtrate wasdiluted with EtOAc, washed with brine, dried (MgSO₄) and evaporated. Theresidue obtained was triturated in boiling methanol. After cooling, theresulting solid was collected by filtration and dried under high vacuumto provide 692 mg (52%) of the title compound as a light-green solid. ¹HNMR (500 MHz, DMSO-d₆): δ 3.67 (s, 3H), 6.58 (d, 1H, J=12 Hz), 6.89 (s,1H), 6.95 (br s, 2H), 7.26 (s, 1H), 7.99 (d, 1H, J=8 Hz), 8.03 (d, 1H,J=8 Hz), 8.04 (d, 1H, J=8 Hz), 8.50 (s, 1H), 10.86 (s, 1H); LCMS (m/z):422/424 [C₁₆H₁₃BrFN₅OS+H]⁺.

Step D{6-[2-Amino-4-fluoro-5-(1-methyl-1H-imidazol-2-ylsulfanyl)-benzoylamino]-pyridin-3-yl}-methyl-phosphinicacid isopropyl ester

A mixture of2-amino-N-(5-bromo-pyridin-2-yl)-4-fluoro-5-(1-methyl-1H-imidazol-2-ylsulfanyl)-benzamide(346 mg, 0.82 mmol), isopropyl methylphosphinate (0.256 mL, 2.05 mmol),[1,1′-bis(diphenylphosphino)ferrocene]palladium (II) dichloride (60 mg,0.082 mmol) and 8 mL of toluene was degassed by bubbling N₂ through itfor 2 min, then triethylamine (0.285 mL, 2.05 mmol) and triethylsilane(0.033 mL, 0.205 mmol) were added and the mixture microwave heated at150° C. for 10 min. The solvent was evaporated and the residue dissolvedin CH₂Cl₂, washed with brine, dried (MgSO₄) and evaporated. The residuewas adsorbed to SiO₂ and subjected to MPLC on a 12 g SiO₂ column elutingwith % EtOAc in hexanes (time): 75 (8 min), 85 (10 min), 90 (10 min),100 (20 min), then % MeOH in EtOAc (time): 1 (10 min), 2 (10 min) toprovide 60 mg (16%) of the title compound. ¹H NMR (500 MHz, DMSO-d₆): δ1.11 (d, 3H, J=6 Hz), 1.29 (d, 3H, J=6 Hz), 1.69 (d, 3H, J=15 Hz), 3.68(s, 3H), 4.40 (septet, 1H, J=6 Hz), 6.60 (d, 1H, J=12 Hz), 6.90 (d, 1HJ=1 Hz), 6.98 (s, 2H), 7.27 (d, 1H, J=1 Hz), 8.02 (d, 1H, J=8 Hz), 8.12(td, 1H, J=7, 3 Hz), 8.17 (dd, 1H, J=7, 2 Hz), 8.67 (dt, 1H, J=5, 1 Hz),11.02 (s, 1H); LCMS (m/z): 464.1 [C₂₀H₂₃FN₅O₃PS+H]⁺.

Example 16{5-[3-Isopropoxy-5-(4-methanesulfonyl-phenoxy)-benzoylamino]-pyrazin-2-ylmethyl}-phosphonicacid hydrobromide salt

In a similar manner to Example 1, a mixture of diethyl{2-[3-isopropoxy-5-(4-methanesulfonyl-phenoxy)-benzoylamino]-pyrazin-5-ylmethyl}phosphonate(29 mg, 0.05 mmol) and bromotrimethylsilane (0.13 mL, 1.0 mmol) in 1 mLof CH₂Cl₂ was stirred for 16 h at rt and the solvents evaporated. Theresidue was sonicated in 1 mL of CH₃CN, the solvent evaporated, theresidue sonicated in 1 mL CH₃CN and 2 mL water, the solutionconcentrated by evaporation followed by lyophilization to provide 28 mg(76%) of the title compound as an amorphous solid. ¹H NMR (500 MHz,DMSO-d₆): δ 1.31 (d, 6H1, J=6 Hz), 3.21 (s, 3H), 3.23 (d, 2H, J=22 Hz),4.78 (septet, 1H, J=6 Hz), 6.97 (t, 1H, J=2 Hz), 7.25 (d, 2H, J=8 Hz),7.36 (t, 1H, J=2 Hz), 7.52 (t, 1H, J=2 Hz), 7.95 (d, 2H, J=8 Hz), 8.39(t, 1H, J=2 Hz), 9.25 (d, 1H, J=1 Hz), 11.13 (s, 1H); LCMS (m/z): 522.4[C₂₂H₂₄N₃O₈PS+H]⁺. Anal. caled. for (C₂₂H₂₄N₃O₈PS+2HBr+3H₂O): C, 35.84;H, 4.37; N, 5.70. Found: C, 35.59; H, 4.19: N, 5.41.

Intermediates for the preparation of Example 16 were prepared accordingto Route 6, as described below.

Route 6

Step AN-(5-Hydroxymethyl-pyrazin-2-yl)-3-isopropoxy-5-(4-methanesulfonylphenoxy)-benzamide

To a solution of ethyl5-[3-isopropoxy-5-(4-methanesulfonyl-1-phenoxy)-benzoylamino]-pyrazine-2-carboxylicacid ethyl ester (1.00 g, 2 mmol, prepared in a similar manner toExample 6 from the appropriate intermediates with modifications evidentto an individual skilled in the art) in 20 mL of dichloroethane at 0° C.was added 8 mL of a 1 M solution of diisobutylaluminum hydride in hexaneand the resulting solution stirred for 16 h at rt. It was then dilutedwith CH₂Cl₂ and washed with 1 M aqueous NaHSO₄, water, brine, dried(MgSO₄) and evaporated. The residue was adsorbed to SiO₂ and subjectedto MPLC on a 80 g SiO₂ column eluting with % EtOAc in hexanes (time):35-65 (25 min ramp) to provide 296 mg (32%) of the title compound. ¹HNMR (500 MHz, DMSO-d₆): δ 1.31 (d, 6H, J=6 Hz), 3.22 (s, 3H), 4.62 (d,2H, J=6 Hz), 4.79 (septet, 1H, J=6 Hz), 5.55 (t, 1H, J=6 Hz), 6.97 (t,1H, J=2 Hz), 7.26 (d, 2H, J=8 Hz), 7.36 (t, 1H, J=2 Hz), 7.52 (t, 1H,J=2 Hz), 7.94 (d, 2H, J=8 Hz), 8.50 (t, 1H, J=2 Hz), 9.29 (d, 1H, J=1Hz), 11.17 (s, 1H); LCMS (m/z): 458.4 [C₂₂H₂₃N₃O₆S+H]⁺.

Step B Diethyl{2-[3-Isopropoxy-5-(4-methanesulfonylphenoxy)benzoylamino]pyrazin-5-ylmethyl}phosphonate

To a solution ofN-(5-hydroxymethyl-pyrazin-2-yl)-3-isopropoxy-5-(4-methanesulfonyl-phenoxy)-benzamide(130 mg, 0.28 mmol) in 2.8 mL of dichloroethane was added 0.56 mL of a 1M solution of PBr₃ in CH₂Cl₂ and the solution stirred for 4 h at rt.Then triethylphosphite (0.5 mL, 2.8 mmol) was added and the resultingsolution microwave heated at 120° C. for 5 min. Then the mixture wasdiluted with CH₂Cl₂ and washed with aqueous NaHCO₃, brine, dried (MgSO₄)and evaporated. The residue was adsorbed to SiO₂ and subjected to MPLCon a 12 g SiO₂ column eluting with % EtOAc in hexanes (time): 65-95 (30min ramp) to provide 33 mg (20%) of the title compound. ¹H NMR (500 MHz,DMSO-d₆): δ 1.19 (t, 6H, J=6 Hz), 1.30 (d, 6H, J=6 Hz), 3.22 (s, 3H),3.50 (d, 2H, J=21 Hz), 4.02 (m, 4H), 4.78 (septet, 1H, J=6 Hz), 6.97 (t,1H, J=2 Hz), 7.25 (d, 2H, J=8 Hz), 7.35 (t, 1H, J=2 Hz), 7.51 (t, 1H,J=2 Hz), 7.95 (d, 2H, J=8 Hz), 8.41 (dd, 1H, J=1, 2 Hz), 9.29 (d, 1H,J=1 Hz), 11.17 (s, 1H); LCMS (m/z): 578.6 [C₂₆H₃₂N₃O₈PS+H]⁺.

Example 17{4-[3-(1-Methyl-1H-imidazol-2-ylsulfanyl)-5-(thiazol-2-ylcarbamoyl)-phenoxy]-phenyl}-phosphonicacid hydrobromide salt

In a manner similar to Example 1, a mixture of{4-[3-(1-methyl-1H-imidazol-2-ylsulfanyl)-5-(thiazol-2-ylcarbamoyl)-phenoxy]-phenyl}-phosphonicacid diisopropyl ester (58 mg, 0.10 mmol) and bromotrimethylsilane (0.27mL, 2.03 mmol) in 2 mL CH₂Cl₂ was stirred for 16 h at rt. The solventevaporated, the residue dissolved in CH₃CN and then the solventevaporated, and the residue sonicated in a mixture of 1 mL CH₃CN and 0.1mL water. The resulting white solid was collected by filtration anddried under high vacuum to provide 30 mg (61%) of the title compound. ¹HNMR (500 MHz, DMSO-d₆): δ 3.84 (s, 3H), 7.14 (dd, 2H, J=8, 3 Hz), 7.30(d, 1H, J=4 Hz), 7.38 (br s, 1H), 7.55 (d, 1H, J=4 Hz), 7.72 (d, 1H, J=1Hz), 7.72 (dd, 2H, J=12, 8 Hz), 7.76 (br s, 1H), 7.80 (t, 1H, J=2 Hz),7.88 (d, 1H, J=1 Hz); LCMS (m/z): 489.5 [C₂₀H₁₇N₄O₅PS₂+H]⁺. Anal. calcd.for (C₂₀H₁₇N₄O₅PS₂+1.5 HBr+1.5H₂O): C, 37.72; H, 3.40; N, 8.80. Found:C, 37.94; H, 3.44; N, 8.58.

Intermediates for the preparation of Example 17 were prepared accordingto Route 7, as described below.

Route 7

Step A 3-Fluoro-5-(1-methyl-1H-imidazol-2-ylsulfanyl)-benzonitrile

A mixture of NaH (60%, 3.16 g, 79 mmol) in oil was rinsed with drypentane by syringe (3×10 mL) and excess solvent removed under a steam ofN₂. Solid 2-mercapto-1-methylimidazole (9.03 g, 79 mmol) was addedfollowed by 200 mL of DMF under ice-bath cooling which resulted in avigorous evolution of gas. After 15 min, solid 3,5-difluorobenzonitrile(10.00 g, 71.9 mmol) was added and the resulting mixture stirred for 5days at 60° C. After cooling to rt the mixture was diluted with 500 mLether and 500 mL water. The resulting white solid was collected byfiltration and triturated in 50 mL of boiling ethanol which aftercooling to rt was collected by filtration and dried under high vacuum toprovide 1.54 g (9%) of3-fluoro-5-(1-methyl-1H-imidazol-2-ylsulfanyl)-benzonitrile: ¹H NMR (500MHz, DMSO-d₆): δ 3.54 (s, 3H), 7.40 (d, 1H, J=2 Hz), 7.52 (d, 1H, J=2Hz), 7.96 (dt, 1H, J=8, 2 Hz), 8.13 (m, 1H), 8.15 (dt, 1H, J=8, 2 Hz);LCMS (m/z): 234.1 [C₁₁H₈FN₃S+H]⁺. The ether layer was separated from thefiltrate and washed with water, brine, dried (MgSO₄) and evaporated. Theresidue was recrystallized from 30 mL of boiling ethanol to providedafter filtration and drying a further 1.57 g (9%) which by HPLC was 75%enriched in 3-fluoro-5-(1-methyl-1H-imidazol-2-ylsulfanyl)-benzonitrile.The filtrate was evaporated to provide 5 g of crude product enriched inthe title compound. This was adsorbed to 15 g of SiO₂ from CH₂Cl₂ andsubjected to MPLC on a 120 g column of SiO₂ eluting with % EtOAc inhexanes (time): 35% (10 min), 35-50% (5 min ramp), 50% (20 min) whichprovided 1.2 g (7%) of 90% HPLC pure title compound as well as 1.96 g(12%) of 98% HPLC pure title compound: ¹H NMR (500 MHz, DMSO-d₆): δ 3.66(s, 3H), 7.20 (d, 1H, J=1 Hz), 7.22 (ddd, 1H, J=8, 3, 2 Hz), 7.34 (t,1H, J=2 Hz), 7.55 (d, 1H, J=1 Hz), 7.72 (ddd, 1H, J=8, 3, 2 Hz); LCMS(m/z): 234.1 [C₁₁H₈FN₃S+H]⁺.

Step B3-(4-Iodo-phenoxy)-5-(1-methyl-1H-imidazol-2-ylsulfanyl)-benzonitrile

A mixture of NaH (60%, 312 mg, 7.8 mmol) in oil was rinsed with drypentane by syringe (3×3 mL) and excess solvent removed under a steam ofN₂. Solid 4-iodophenol (1.72 g, 7.8 mmol) was added followed by 16 mL ofDMF under ice-bath cooling which resulted in a vigorous evolution ofgas. After 15 min, solid3-fluoro-5-(1-methyl-1H-imidazol-2-ylsulfanyl)-benzonitrile (910 mg, 3.9mmol) was added and the resulting mixture microwave heated at 160° C.for 10 min. After cooling to rt, the mixture was diluted with ether and3 M aqueous NaOH and shaken. The organic layer was washed with water,brine, dried (MgSO₄) and evaporated. The resulting 1.8 g of residue wasadsorbed to 4.5 g SiO₂ from CH₂Cl₂ and subjected to MPLC on a 40 gcolumn of SiO₂ eluting with % EtOAc in hexanes (time): 33% (10 min),35-50% (20 min ramp) which provided 1.60 g (95%) of the title compound:¹H NMR (500 MHz, DMSO-d₆): δ 3.63 (s, 3H), 6.82 (dd, 1H, J=2, 1 Hz),6.90 (d, 2H, J=8 Hz), 7.13 (d, 1H, J=1 Hz), 7.26 (t, 1H, J=2 Hz), 7.37(dd, 1H, J=2, 1 Hz), 7.50 (d, 1H, J=1 Hz), 7.75 (d, 2H, J=8 Hz); LCMS(m/z): 434.3 [C₁₇H₁₂IN₃OS+H]⁺.

Step C 3-(4-Iodo-phenoxy)-5-(1-methyl-1H-imidazol-2-ylsulfanyl)-benzoicacid

A mixture of3-(4-iodo-phenoxy)-5-(1-methyl-1H-imidazol-2-ylsulfanyl)-benzonitrile(1.60 g, 3.69 mmol), 12 mL of ethanol, 1.2 mL of water and 1 mL of 50%w/w NaOH in water (18.45 mmol) was microwave heated at 130° C. for 5 minand then cooled to rt. The mixture was concentrated by evaporation anddiluted with 20 mL of water, then with stirring, 20 mL of 1 M aqueousNaHSO₄ was added. The resulting solid was collected by filtration anddried at 0.1 mm/23° C. for 16 h to provide 1.5 g (90%) of the titlecompound as a white solid: ¹H NMR (500 MHz, DMSO-d₆): δ 3.63 (s, 3H),6.91 (d, 2H, J=8 Hz), 6.94 (t, 1H, J=2 Hz), 7.14 (d, 1H, J=1 Hz), 7.21(dd, 1H, J=2, 1 Hz), 7.28 (dd, 1H, J=2, 1 Hz), 7.51 (d, 1H, J=1 Hz),7.75 (d, 2H, J=8 Hz); LCMS (m/z): 453.5 [C₁₇H₁₃IN₂O₃S+H]⁺,

Step D 3-(4-Iodo-phenoxy)-5-(1-methyl-1H-imidazol-2-ylsulfanyl)-benzoicacid methyl ester

A mixture of3-(4-iodo-phenoxy)-5-(1-methyl-1H-imidazol-2-ylsulfanyl)-benzoic acid(1.4 g, 3.1 mmol), K₂CO₃ (856 mg, 6.2 mmol), iodomethane (0.29 mL, 4.65mmol) and 16 mL of DMF were stirred for 2 h at rt. Then the mixture wasdiluted with ether and washed with water, brine, dried (MgSO₄) andevaporated. The residue was adsorbed to SiO₂ from CH₂Cl₂ and subjectedto MPLC on a 40 g column of SiO₂ eluting with % EtOAc in hexanes (time):33% (10 min), 35-50% (20 min ramp) which provided 1.32 g (91%) of thetitle compound: ¹H NMR (500 MHz, DMSO-d₆): δ 3.63 (s, 3H), 3.79 (s, 3H),6.91 (d, 2H, J=8 Hz), 6.96 (dd, 1H, J=2, 1 Hz), 7.14 (d, 1H, J=1 Hz),7.23 (dd, 1H, J=2, 1 Hz), 7.32 (t, 1H, J=1 Hz), 7.51 (d, 1H, J=1 Hz),7.75 (d, 2H, J=8 Hz); LCMS (m/z): 467.4 [C₁₈H₁₅N₂O₃S+H]⁺.

Step E3-[4-(Diisopropoxy-phosphoryl)-phenoxy]-5-(1-methyl-1H-imidazol-2-ylsulfanyl)-benzoicacid methyl ester

Conducted as described for STEP D, Example 15 only substitutingdiisopropyl phosphite for isopropyl methylphosphinate. From3-(4-iodo-phenoxy)-5-(1-methyl-1H-imidazol-2-ylsulfanyl)-benzoic acidmethyl ester (650 mg, 1.39 mmol), 292 mg (42%) of the title compound wasisolated: ¹H NMR (500 MHz, DMSO-d₆): δ 1.19 (d, 6H, J=6 Hz), 1.28 (d,6H, J=6 Hz), 3.64 (s, 3H), 3.80 (s, 3H), 4.56 (m, 2H), 7.05 (t, 1H, J=2Hz), 7.13 (d, 1H, J=1 Hz), 7.15 (dd, 2H, J=8, 3 Hz), 7.33 (dd, 1H, J=2,1 Hz), 7.38 (t, 1H, J=1 Hz), 7.50 (d, 1H, J=1 Hz), 7.73 (dd, 2H, J=12, 8Hz); LCMS (m/z): 505.7 [C₂₄H₂₉N₂O₆PS+H]⁺.

Step F3-[4-(Diisopropoxy-phosphoryl)-phenoxy]-5-(1-methyl-1H-imidazol-2-ylsulfanyl)-benzoicacid

A mixture of3-[4-(diisopropoxy-phosphoryl)-phenoxy]-5-(1-methyl-1H-imidazol-2-ylsulfanyl)-benzoicacid methyl ester (292 mg, 0.58 mmol), 3 mL of dioxane, 3 mL of waterand 1.2 mL of 1 M aqueous NaOH was stirred for 2 h at rt, diluted withwater, washed with EtOAc, the aqueous layer pH lowered to 4 with 1 MNaHSO₄, the aqueous layer extracted with 4:1 CH₂Cl₂/MeOH. The organicextract dried (MgSO₄) and evaporated to provide 234 mg (82%) of thetitle compound: ¹H NMR (500 MHz, DMSO-d₆): δ 1.18 (d, 6H, J=6 Hz), 1.28(d, 6H, J=6 Hz), 3.64 (s, 3H), 4.55 (m, 2H), 7.03 (t, 1H, J=2 Hz), 7.13(s, 1H), 7.15 (dd, 2H, J=8, 3 Hz), 7.31 (dd, 1H, J=2, 1 Hz), 7.35 (t,1H, J=1 Hz), 7.50 (s, 1H), 7.72 (dd, 2H, J=12, 8 Hz); LCMS (m/z): 491.9[C₂₃H₂₇N₂O₆PS+H]⁺.

Step G{4-[3-(1-Methyl-1H-imidazol-2-ylsulfanyl)-5-(thiazol-2-ylcarbamoyl)-phenoxy]-phenyl}-phosphonicacid diisopropyl ester

A mixture of diisopropyl3-[4-(diisopropoxy-phosphoryl)-phenoxy]-5-(1-methyl-1H-imidazol-2-ylsulfanyl)-benzoicacid (68 mg, 0.139 mmol), 2-aminothiazole (28 mg, 0.277 mmol), HATU (66mg, 0.174 mmol), DIEA (0.058 mL, 0.35 mmol) and 0.7 mL of DMF werestirred for 16 h ant rt, diluted with CH₂Cl₂, washed with water, brine,dried and evaporated. The residue was adsorbed to SiO₂ and subjected toMPLC on a 12 g column of SiO₂ eluting with % MeOH in CH₂Cl₂ (time): 1%(5 min), 2.5% (10 min), 5% (10 min) which provided 50 mg (63%) of thetitle compound: ¹H NMR (500 MHz, DMSO-d₆): δ 1.20 (d, 6H, J=6 Hz), 1.28(d, 6H, J=6 Hz), 3.66 (s, 3H), 4.56 (m, 2H), 6.95 (t, 1H, J=2 Hz), 7.13(d, 1H, J=1 Hz), 7.15 (dd, 2H, J=8, 3 Hz), 7.30 (br s, 1H), 7.50 (d, 1H,J=1 Hz), 7.55 (d, 1H, J=3 Hz), 7.60 (br s, 1H), 7.67 (br s, 1H), 7.73(dd, 2H, J=12, 8 Hz); LCMS (m/z): 573.7 [C₂₆H₂₉N₄O₅PS₂+H]⁺.

Example 18{4-[3-(5-Chloro-thiazol-2-ylcarbamoyl)-5-(1-methyl-1H-imidazol-2-ylsulfanyl)-phenoxy]-phenyl}-phosphonicacid hydrobromide salt

Prepared as described in Example 17, Route 6, with modifications evidentto an individual skilled in the art. ¹H NMR (500 MHz, DMSO-d₆): δ 3.78(s, 3H), 7.14 (dd, 2H, J=8, 3 Hz), 7.25 (br s, 1H), 7.57 (br s, 1H),7.62 (s, 1H), 7.68 (t, 1H, J=1 Hz). 7.72 (br s, 1H), 7.72 (dd, 2H, J=12,8 Hz), 7.76 (br s, 1H); LCMS (m/z): 489.5 [C₂₀H₁₆ClN₄O₅PS₂+H]⁺. Anal.calcd. for (C₂₀H₁₆ClN₄O₅PS₂+1 HBr+0.6H₂O): C, 39.08; H, 2.98; N, 9.12.Found: C, 39.08; H, 3.16; N, 9.12.

Example 19{4-[3-(1-Methyl-1H-imidazol-2-ylsulfanyl)-5-(thiazol-2-ylcarbamoyl)-phenoxy]-phenyl}-phosphinicacid bis-sodium salt

A mixture of3-(4-iodo-phenoxy)-5-(1-methyl-1H-imidazol-2-ylsulfanyl)-N-thiazol-2-yl-benzamide(140 mg, 0.26 mmol), anilinium hypophosphite (83 mg, 0.52 mmol),[1,1′-bis(diphenylphosphino)ferrocene]palladium (II) dichloride (10 mg,0.013 mmol) and 2.6 mL of CH₃CN was degassed by bubbling N₂ through itfor 2 min, then triethylamine (0.11 mL, 0.78 mmol) was added and themixture microwave heated at 140° C. for 10 min. The mixture was dilutedwith water and concentrated to a suspension by evaporation. Aqueous 3 MNaOH was added until the solution was pH 12. Then 1 M aqueous NaHSO₄ wasadded until the solution was pH 3 and the resulting tan solid collected.The solid was dissolved in water with the addition of 3 M NaOH andsubjected to MPLC on a 25 g C18 reverse phase SiO₂ column. Elution with% CH₃CN in water (time): 5% (5 min), 5-75% (15 min ramp) provided 11 mg(7%) of the title compound: ¹H NMR (500 MHz, DMSO-d₆): δ 3.65 (s, 3H),6.79 (t, 1H, J=2 Hz), 6.99 (dd, 2H, J=8, 2 Hz), 7.13 (d, 2H, J=1 Hz),7.25 (br s, 1H), 7.39 (d, 1H, J=467 Hz), 7.50 (d, 1H, J=1 Hz), 7.52-7.54(m, 3H), 7.56 (dd, 2H, J=11, 8 H1); LCMS (m/z): 473.6[C₂₀H₁₇N₄O₄PS₂+H]⁺. Anal. calcd. for (C₂₀H₁₅N₄Na₂O₄PS₂+2H₂O): C, 43.48;H, 3.47; N, 10.14. Found: C, 43.85; H, 3.47; N, 9.97.

The intermediate for the preparation of Example 19 were preparedaccording to the following procedure.

Step A4-(3-(1-Methylimidazol-2-ylthio)-5-(triazol-2-ylcarbamoyl)phenoxy)phenyliodine

The title compound was prepared from3-(4-Iodo-phenoxy)-5-(1-methyl-1H-imidazol-2-ylsulfanyl)-benzoic acid(Example 17, STEP C) according to the method described in Example 17,STEP G. ¹H NMR (300 MHz, DMSO-d₆): δ 3.65 (s, 3H), 6.85 (t, 1H, J=2 Hz),6.92 (d, 2H, J=8 Hz), 7.14 (d, 1H, J=1 Hz), 7.29 (d, 1H, J=3 Hz), 7.51(m, 1H), 7.51 (d, 1H, J=1 Hz), 7.53 (m, 1H), 7.54 (d, 1H, J=3 Hz), 7.74(d, 2H, J=8 Hz), 12.75 (s, 1H); LCMS (m/z): 535.4 [C₂₀H₁₅N₄O₂S₂+H]⁺.

Example 20{4-[3-(5-Chloro-thiazol-2-ylcarbamoyl)-5-(1-methyl-1H-imidazol-2-ylsulfanyl)-phenoxy]-phenyl}-phosphinicacid bis-sodium salt

Prepared according to the method described in Example 19 withmodifications evident to an individual skilled in the art. ¹H NMR (500MHz, DMSO-d₆): δ 3.63 (s, 3H), 6.64 (t, 1H, J=2 Hz), 6.96 (dd, 2H, J=8,2 Hz), 7.09 (s, 1H), 7.11 (d, 2H, J=1 Hz), 7.39 (d, 1H, J=469 Hz), 7.44(dd, 1H, J=2, 1 Hz), 7.47 (d, 1H, J=1 Hz), 7.56 (dd, 2H, J=11, 8 Hz),7.58 (t, 1H, J=2 Hz); LCMS (m/z): 507.7 [C₂₀H₁₆ClN₄O₄PS₂H]+. Anal.calcd. for (C₂₀H₁₄ClN₄Na₂O₄PS₂+5H₂O); C, 37.48; H, 3.77; N. 8.74. Found:C, 37.71; H, 2.99; N, 8.43.

Example 21[({2-[3-Isopropoxy-5-(4-methanesulfonyl-phenoxy)-benzoylamino]-thiazole-4-carbonyl}-amino)-methyl]-phosphonicacid

{[(2-Amino-thiazole-4-carbonyl)-amino]-methyl}-phosphonic acid diethylester is prepared according to Route 7, as described below.

Route 7

To a solution of 3-isopropoxy-5-(4-methanesulfonyl-phenoxy)-benzoic acidmethyl ester (prepared as in Example 6 Step A) (6.50 g, 17.8 mmol) inTHF (120 mL) was added EtOH (80 mL) and water (40 mL) at roomtemperature. Sodium hydroxide solution (1.0 M, 36.0 mL) was added slowlywith some external cooling, if needed. The mixture was stirred at roomtemperature overnight. On the second day organic solvents were removedby evaporation. The residue was partitioned between ether and water.After the ether layer was discarded, the aqueous layer was acidifiedwith HCl (6.0 M, ˜6.0 mL) to pH<2, and extracted with EtOAc three times.Combined EtOAc layers were washed with brine, dried with anhydrousMgSO₄, filtered, and concentrated to give3-isopropoxy-5-(4-methanesulfonyl-phenoxy)-benzoic acid (6.40 g, 100%)as a white solid. ¹H NMR (300 MHz, CDCl₃): δ 9.91 (s, 1H), 7.93 (d, J=9Hz, 2H), 7.23 (m, 1H), 7.14 (d, J=9 Hz, 2H), 7.10 (m, 1H), 6.85 (m, 1H),4.57-4.65 (m, 1H), 3.01 (s, 3H), 1.37 (d, J=6 Hz, 6H).

The above prepared 3-isopropoxy-5-(4-methanesulfonyl-phenoxy)-benzoicacid is coupled with{[(2-amino-thiazole-4-carbonyl)-amino]-methyl}-phosphonic acid diethylester following the procedure described in Example 1, Step D to give[({2-[3-isopropoxy-5-(4-methanesulfonyl-phenoxy)-benzoylamino]-thiazole-4-carbonyl}-amino)-methyl]-phosphonicacid diethyl ester.

The above[({2-[3-isopropoxy-5-(4-methanesulfonyl-phenoxy)-benzoylamino]-thiazole-4-carbonyl}-amino)-methyl]-phosphonicacid diethyl ester is converted to the title compound following theprocedure described in Example 2.

Example 22[({2-[3-Isopropoxy-5-(4-methanesulfonyl-phenoxy)-benzoylamino]-4-methyl-thiazole-5-carbonyl}-amino)-methyl]-phosphonicacid

{[(2-Amino-4-methyl-thiazole-5-carbonyl)-amino]-methyl}-phosphonic aciddiethyl ester is prepared according to Route 8, as described below.

Route 8

The title compound is prepared from{[(2-amino-4-methyl-thiazole-5-carbonyl)-amino]-methyl}-phosphonic aciddiethyl ester and 3-isopropoxy-5-(4-methanesulfonyl-phenoxy)-benzoicacid in a similar manner to Example 21.

Example 23{4-[3-Isopropoxy-5-(thiazol-2-ylcarbamoyl)-benzyl]-phenyl}-phosphonicacid

The title compound was prepared from{4-[3-isopropoxy-5-(thiazol-2-ylcarbamoyl)-benzyl]-phenyl}-phosphonicacid diisopropyl ester according to the method described in Example 3.¹H NMR (300 MHz, DMSO-d₆): δ 7.62 (dd, J=8, 13 Hz, 2H), 7.56 (d, J=4 Hz,1H), 7.54 (m, 1H), 7.50 (m, 1H), 7.37 (dd, J=3, 8 Hz, 2H), 7.27 (d, J=4Hz, 1H), 7.02 (m, 1H), 4.68-4.76 (m, 1H), 4.00 (s, 2H), 1.28 (d, J=6 Hz,6H); LC-MS (m/z): 433.6 [C20H21N2O5PS+H]⁺. Anal. Calcd. for(C20H21N2O5PS): C, 55.55; H, 4.89; N, 6.48. Found: C, 55.49; H, 4.82; N,6.38.

Intermediates for the preparation of Example 23 were prepared accordingto Route 10, as described below, and Route 3, with modifications evidentto an individual skilled in the art.

Route 10

Step A 3-(4-Bromo-benzoyl)-5-isopropoxy-benzoic acid methyl ester

To a solution of 5-isopropoxy-isophthalic acid monomethyl ester (1.90 g,7.98 mmol) in DCM (50 mL) was added (COCl)₂ (1.39 mL, 16.9 mmol) and DMF(0.03 mL, 0.400 mmol) at rt. After stirring at rt for 2 hr, the mixturewas concentrated. The resulting residue was azeotroped with 50 mLanhydrous toluene and then re-dissolved in Et₂O (40 mL). Palladiumbis(dibenzylideneacetone) (229 mg, 0.400 mmol), copper (I)thiophene-2-carboxylate (1.52 g, 7.98 mmol), triphenylphosphine (209 mg,0.798 mmol), and 4-bromophenylboronic acid (3.20 g, 16.0 mmol) wereadded to the reaction flask. The resulting mixture was stirred at rt for3 hr, filtered through a pad of Celite, rinsed with Et₂O. The combinedEt₂O layers were concentrated. The residue was purified by silica gelflash chromatography (6×25 cm, hexane/EtOAc, v/v=5:1, 3:1). Fractionscontaining the coupling product were pooled and concentrated to give thetitle compound (2.60 g, 86%) as a yellow oil. ¹H NMR (300 MHz, CDCl₃): δ7.91 (m, 1H), 7.77 (m, 1H), 7.63-7.69 (m, 3H), 7.48 (m, 1H), 7.38-7.43(m, 1H), 4.57 (m, 1H), 3.92 (s, 3H), 1.35 (d, J=6 Hz, 6H).

Step B 3-[4-(Diisopropoxy-phosphoryl)-benzoyl]-5-isopropoxy-benzoic acidmethyl ester

The title compound was prepared from3-(4-bromo-benzoyl)-5-isopropoxy-benzoic acid methyl ester in a methodsimilar to Step D of Example 3 with modifications evident to anindividual skilled in the art. ¹H NMR (300 MHz, CDCl₃): δ 7.91-7.98 (m,3H), 7.83 (dd, J=8, 4 Hz, 2H), 7.78 (m, 1H), 7.51 (m, 1H), 4.65-4.79 (m,3H), 3.92 (s, 3H), 1.40 (d, J=6 Hz, 6H), 1.36 (d, J=6 Hz, 6H), 1.27 (d,J=6 Hz, 12H).

Step C 3-[4-(Diisopropoxy-phosphoryl)-benzyl]-5-isopropoxy-benzoic acidmethyl ester

To a solution of3-[4-(diisopropoxy-phosphoryl)-benzoyl]-5-isopropoxy-benzoic acid methylester (750 mg, 1.62 mmol) in MeOH (30 mL) was added NaBH₄ (120 mg, 3.17mmol) at rt. Stirred at rt overnight. On the second day, the mixture wasconcentrated. The residue was partitioned between EtOAc/HCl (0.1 M) andthe organic layer was separated, washed with brine, dried, andconcentrated. The resulting residue was dissolved in a mixture ofEtOAc/EtOH (20 mL, v/v=10:1) and hydrogenated over Pd/C (10%, 200 mg)using a Parr apparatus overnight. Then the mixture was filtered througha Celite plug. The filtrate was concentrated, azeotroped with CH₂Cl₂ togive the title compound (720 mg, 100%). ¹H NMR (300 MHz, CDCl₃): δ 7.72(dd, J=13, 8 Hz, 2H), 7.45 (m, 1H), 7.40 (m, 1H), 7.25 (dd, J=8, 4 Hz,2H), 6.87 (m, 1H), 4.62-4.70 (m, 2H), 4.53-4.61 (m, 1H), 3.88 (s, 3H),1.36 (d J=6 Hz, 6H), 1.32 (d J=6 Hz, 6H), 1.22 (d, J=6 Hz, 12H).

Example 24 2,2-Dimethyl-propionic acidhydroxy-{4-[3-isopropoxy-5-(thiazol-2-ylcarbamoyl)-phenoxy]-phenyl}-phosphinoyloxymethylester, sodium salt

A mixture of{4-[3-isopropoxy-5-(thiazol-2-ylcarbamoyl-)phenoxy]-phenyl}-phosphonicacid (250 mg, 0.58 mmol) and 0.7 mL of saturated aqueous NaHCO₃ in 4 mLof DMF were stirred at rt for 15 min and then iodomethyl pivalate (0.088mL, 0.58 mmol) was added. The mixture was stirred at rt for 3 h, then0.46 mL of saturated aqueous NaHCO₃ was added. After a further 2 h, moreiodomethyl pivalate (0.044 mL, 0.29 mmol) was added. After stirring atrt a further 16 h, and 0.1 mL of 5 M NaOH was added. The solvents wereevaporated under high vacuum and the residue dissolved in 1:1acetonitrile/water and subjected to MPLC purification through a 25 g C18column eluting with % acetonitrile in water (time): 10 (5 min), 10-30 (6min), 30 (6 min). Lyophilization of the eluent containing the desiredproduct provided 81 mg (23%) of the title compound as an amorphoussolid: ¹H NMR (500 MHz, DMSO-d₆): δ 0.91 (s, 9H), 1.29 (d, 6H, J=6 Hz),4.73 (septet, 1H, J=6 Hz), 5.43 (d, 2H, J=13 Hz), 6.72 (t, 1H, J=2 Hz),6.98 (dd, 2H, J=8, 2 Hz), 7.22 (t, 1H, J=2 Hz), 7.27 (d, 1H, J=3.5 Hz),7.44 (d, 1H, J=2 Hz), 7.55 (d, 1H, J=3.5 Hz), 7.64 (dd, 2H, J=11, 8 Hz);LCMS (m/z): 549.4 [C₂₅H₂₈N₂NaO₈PS+H]⁺. Anal. calcd. for(C₂₅H₂₈N₂NaO₈PS+1.5H₂O): C, 50.25; H, 5.23; N, 4.69. Found: C, 50.29; H,5.16; N, 4.69.

Example 25{5-[3-Isopropoxy-5-(4-methanesulfonyl-phenoxy)-benzoylamino]-pyrazin-2-ylmethyl}-methyl-phosphinicacid hydrobromide salt

Prepared as described for Example 16 with substitution of diethylmethylphosphonite for the triethylphosphite used in Step B, Route 10. ¹HNMR (500 MHz, DMSO-d₆): δ 1.31 (d, 6H, J=6 Hz), 1.36 (d, 3H, J=15 Hz),3.21 (s, 3H), 3.30 (d, 2H, J=17 Hz), 4.78 (septet, 1H, J=6 Hz), 6.97 (t,1H, J=2 Hz), 7.25 (d, 2H, J=8 Hz), 7.35 (t, 1H, J=2 Hz), 7.51 (t, 1H,J=2 Hz), 7.95 (d, 2H, J=8 Hz), 8.39 (t, 1H, J=1 Hz), 9.28 (d, 1H, J=1Hz), 11.14 (s, 1H); LCMS (m/z): 520.6 [C₂₃H₂₆N₃O₇PS+H]⁺. Anal. calcd.for (C₂₃H₂₆N₃O₇PS+2 HBr+4H₂O): C, 36.67; H, 4.82; N, 5.58. Found: C,37.04; H, 4.72; N, 5.18.

Example 26{4-[3-Isopropoxy-5-(thiazol-2-ylcarbamoyl)phenoxy]phenyl}phosphonic acidmonomethyl ester

To a solution of{4-[3-isopropoxy-5-(thiazol-2-ylcarbamoyl)-phenoxy]-phenyl}-phosphonicacid (Example 3) (100 mg, 0.225 mmol) in DMF (2 mL) and pyridine (300μL) was added methanol (91 μL, 2.25 mmol) and EDCI (47 mg, 0.247 mmol).The resulting mixture was subjected to microwave heating at 130° C. for5 min. Then NaOH (2 mL) was added and the resulting mixture was stirredat rt for 10 min. The residue was partitioned between EtOAc and H₂O. Theaqueous layer was acidified with HCl (6N) to pH 2 and extracted intoEtOAc. The organic layer was washed with brine (2×), dried andconcentrated to give an oil. Water was added (10 mL) until a precipitateformed which was filtered and dried to afford 25 mg (25%) of{4-[3-isopropoxy-5-(thiazol-2-ylcarbamoyl)phenoxy]phenyl}phosphonic acidmonomethyl ester. ¹H NMR (500 MHz, DMSO-d₆): δ 7.71 (dd, J=12, 9 Hz,2H), 7.53 (m, 2H), 7.32 (m, 2H), 7.15 (dd, J=9, 3 Hz, 2H), 6.89 (t, J=3Hz, 1H), 4.76 (m, 1H), 3.52 (d, J=11 Hz, 3H), 1.30 (d, J=6 Hz, 6H); LCMSm/z=449.6 [C₂₀H₂₁N₂O₆PS+H]⁺; Anal. Calcd. for (C₂₀H₂₁N₂O₆PS+0.5H₂O): C,52.51; H, 4.85; N, 6.12. Found: C, 52.54; H, 4.93; N, 6.15.

Example 27{4-[3-Isopropoxy-5-(thiazol-2-ylcarbamoyl)-phenoxy]-phenyl}-phosphinicacid

Prepared from 3-hydroxy-5-isopropoxy-benzoic acid methyl ester (Example1, Route 1, STEP A) in a similar manner to Example 19 from theappropriate intermediates with modifications evident to an individualskilled in the art: ¹H NMR (300 MHz, DMSO-d₆): δ 7.74 (dd J=13, 9 Hz,2H), 7.54 (dd, J=8, 3 Hz, 1H), 7.52 (s, 1H), 7.49 (d, J=547 Hz, 1H),7.31 (m, 2H), 7.20 (dd, J=9, 2 Hz, 2H), 6.90 (t, J=2 Hz, 1H), 4.76 (m,1H), 1.30 (d, J=6 Hz, 6H); LCMS m/z=419.4 [C₁₉H₁₉N₂O₅PS+H]⁺; Anal.Calcd. for (C₁₉H₁₉N₂O₅PS): C, 54.54; H, 4.58; N, 6.70. Found: C, 54.72;H, 4.57; N, 6.46.

Examples 28-54

The following examples were prepared in a similar manner to Example 1from the appropriate intermediates with modifications evident to anindividual skilled in the art:

Mass Spect. 1H NMR δ (DMSO-d₆) & Example Structure (Mode) ElementalAnalysis 28

461.3 (+) 11.05 (br, 1 H), 8.64 (m, 1 H), 8.27 (m 1 H), 8.07-8.14 (m, 1H), 7.35 (dd, J = 5, 2 Hz, 1 H), 7.17- 720 (m, 2 H), 7.95-6.98 (m, 2 H),6.67 (m, 1 H), 4.67-4.75 (m, 1 H), 4.25 (t, J = 6 Hz, 2 H), 3.25 (t, J =6 Hz, 2 H), 1.54 (d, J = 15 Hz, 3 H), 1.26 (d, J = 6 Hz, 6 H) Anal.Calcd. for (C22H25N2O5PS + 0.9 H2O): C, 55.43; H, 5.67; N, 5.88. Found:C, 55.67; H, 5.28, N, 5.62. 29

463.3 (+) 10.90 (br, 1H), 8.62 (m, 1H), 8.18 (m 1 H), 8.01-8.09 (m, 1H), 7.47 (dd, J = 5, 3 Hz, 1 H), 7.31- 7.33 (m, 1 H), 7.21 (m, 1 H),7.17 (m, 1 H), 6.66 (m, 1 H), 4.66-4.74 (m, 1 H), 4.24 (t, J = 7 Hz,2H), 3.05 (t, J = 6 Hz, 2 H), 1.27 (d, J = 6 Hz, 6 H). Anal. Calcd. for(C21H23N2O6PS + 0.5 H2O − 0.4 HBr): C, 50.06; H, 4.88; N, 5.56. Found:C, 49.95; H, 4.92; N, 5.37. 30

489.6 (+) 11.05 (br, 1 H), 8.57 (dd, J = 6.2 Hz, 1 H). 8.28 (d, J = 9Hz, 1H), 8.05 (m, 1 H), 7.47 (dd, J = 5, 3 Hz, 1 H). 7.31 (dd. J = 3, 1Hz, 1 H), 7.20 (m, 1 H), 7.16 (m, 1 H), 7.11 (dd. J = 5, 1 Hz, 1 H),6.67 (m, 1 H), 4.70-4.72 (m, 1 H), 4.24 (t, J = 7 Hz, 2 H), 3.05 (1, J =7 Hz, 2 H), 1.92-1.95 (m, 1 H), 1.26 (d, J = 6 Hz, 6 H), 0.98 (dd, J =17, 8 Hz, 6 H), Anal. Calcd. for (C24H29N2O5PS +0.5 HBr): C, 54.49; H,5.62; N, 5.30. Found: C, 54.44; H, 5.43; N. 4.92. 31

409.1 (+) 11.00 (s, 1 H), 8.57 (m, 1 H), 8.23 (m, 1 H), 8.03 (m, 1H),7.16 (d, J = 1.2 Hz, 2 H), 6.63 (m, 1H), 4.70 (m, 1 H), 3.78 (d, J = 6.6Hz, 2 H), 2.00 (m, 1 H), 1.25 (d, J = 6.3 Hz, 6 H), 0.96 (d, J = 6.9 Hz,6 H). Anal. Calcd. for (C19H25N2O6P + 0.3 HI): C, 51.08; H, 5.71; N,6.27. Found: C, 50.75; H, 5.59; N, 6.13. 32

395.4 (+) 10.99 (s, 1 H), 8.5= (m, 1 H), 8.25 (m, 1 H), 8.02 (m, 1H),7.15 (d, J = 1.8 Hz, 2 H), 6.63 (s, 1H), 4.71 (m, 1 H), 3.96 (m, 2 H),1.70 (m, 2 H), 1.25 (d, J = 6.0 Hz, 6 H), 0.96 (m, 3H). Anal. Calcd. for(C18H123N2O6P + 0.12 HI): C, 52.77; H, 5.69; N, 6.84, Found: C, 52.70;H, 5.44; N, 6.66. 33

435.4 (+) 10.98 (s, 1 H), 8.56 (m, 1 H), 8.23 (m, 1 H), 8.02 (m, 1H),7.15 (d, J = 1.2 Hz, 2 H), 6.63 (m, 1H), 4.70 (m, 1H) 3.88 (d, J = 6.9Hz, 2 H), 2.28 (m, 1H), 1.75 (m, 2 H), 1.56 (m. 4H), 1.33 (m, 2H), 1.25(d, J = 6.0 Hz, 6 H). Anal. Calcd. for (C21H27N2O6P +0.18 HI): C, 55.14;H, 5.98; N, 6.12. Found: C, 55.32; H, .5.98; N, 6.06, 34

463.5 (+) 11.03 (s, 1 H), 8.56 on, 1H), 8.23 (m, 1 H), 8.03 (m, 1 H),7.46 (m, 7.31 (m, 1H), 7.18 (m, 2H), 7.11 (m, 1H), 6.66 (m, 1H), 4.70(m, 1 H), 4.24 (m, 2H), 3.04 (m, 2H), 1.25 (d, J = 6.3 Hz, 6 H). Anal.Calcd. for (C21H23N2O6PS + 0.5 HI): C, 47.91 H, 4.50; N, 5.32 Found: C,48.07; H., 4.69; N, 4.97. 35

393.4 (+) 11.01 (s, 1 H), 8.58 (m, 1 H), 8.21 (m, 1 H), 8.06 (m, 1H),7.12 (d, J = 1.4 Hz, 2H), 6.60 (m, 1H), 4.67 (m, 1 H), 3.93 (m, 2H),1.67 (m, 2 H), 1.51 (d, J = 14.6 Hz, 3 H), 1.22 (d, J = 6.0 Hz, 6H),0.92 (m, 3H). Anal. Calcd. for (C19H25N2O5P + 0.3 HI): C, 52.98; H,5.92; N, 6.50. Found: C, 52.74; H, 6.11; N, 6.56. 36

441.4 (+) 11.11 (s, 1 H), 8.67 (m, 1 H), 8.30 (m, 1 H), 8.13 (m, 1H),7.35 (m, 7H), 6.79(s, 1H), 5.20 (s, 2H), 4.71 (m, 1 H), 1.58 (d, J =14.6 Hz, 3H), 1.23 (d, J = 6.0 Hz, 6H). Anal. Calcd. for (C23H25N2O5P +1.1 HBr): C, 52.18; H, 4.97; N, 5.29. Found: C, 51.82; H, 4.97; N, 5.60.37

407.4 (+) 10.98 (s, 1 H), 8.58 (m, 1 H), 8.20 (m, 1 H), 8.04 (m, 1H),7.09 (d, J = 1.8 Hz, 2H), 6.58 (m, 1H), 4.64 (m, 1 H), 3.72 (d, J = 6.6Hz, 2H), 1.94 (m, 1 H), 1.49 (d, J = 15.0 Hz. 3 H), 1.19 (d, J = 6.0 Hz,6H), 0.90 (d, J = 6.6 Hz, 6H). Anal. Calcd. for (C20H27N2O5P + 0.15HBr): C, 57.39; H, 6.54; N, 6.69. Found: C, 57.46; H, 6.23; N, 6.55. 38

459.4 (+) δ 10.92 (s, 1 H), 8.46 (m, 1 H) 8.05 (m, 1 H), 7.92 (m, 1H),7.22 (m, 6H), 6.57 (m, 1H), 5.02 (s, 2H), 4.54 (m, 1 H), 1.36 (d, J =15.2 Hz, 3H), 1.07 (d, J = 6.0 Hz, 6H) = Anal. Calcd. for(C23H24FN2O5P + 1.0 HBr): C, 51.22; H, 4.67; N, 5.19. Found: C, 51.15;H, 4.47; N, 5.25. 39

433.4 (+) 11.03 (s, 1 H), 8.64 (m, 1 H), 8.26 (m, 1 H), 8.13 (m, HI),7.16 (m, 2 H), 6.64 (m, 1H), 4.71 (m, 1 H), 3.89 (d, J = 6.6 Hz, 2 H),2.29 (m, 1H), 1.75 (m, 2 H), 1.56 (m, 2H), 1.33 (m, 4H), 1.25 (d, J =6.0 Hz, 6 H). Anal. Calcd. for (C22H29N2O5P +0.35 HBr): C, 57.35; H,6.42; N, 6.08. Found: C, 57.11; H, 6.31; N, 6.38 40

462.3 (+) 1.28 (d, 6, JH = 6 Hz), 1.60 (d, 3H, J = 15 Hz), 3.07 (t, 2H,J = 7 Hz), 4.26 (t, 2H, J? 7 Hz). 4.69- 4.77 (m, 1H), 6.71 (t, 1H, J = 2Hz), 7.13 (dd, 1H, J = 5, 2 Hz), 7.23 (dd, 1H, J = 9, 2 Hz), 7.33- 7.34(m, 1H), 7.49 (dd, 1H, J = 5. Hz), 8.78 (s, 1H), 9.54 (d, 1H, J = 1 Hz).11.36 (s, 1H). Anal. Calcd. for (C₂₁H₂₄N₃O₅PS + 0.3H₂0): C, 54.02; H,5.31; N. 9.00. Found: C, 53.96; H, 5.24; N, 8.73. 41

395.4 (+) 10.99 (s, 1 H), 8.59 (d, J = 3.0 Hz, 1 H), 8.23 (d, J = 6.0Hz, 1 H), 8.02 (t, J = 6.0 Hz, 1 H), 7.16 (s, 2 H), 6.60 (s, 1 H), 4.69(m, 2 H), 1.25 (s, 12 H). Anal. Calcd, for (C18H23N2O6P + 0.7 eq H2O) C,53.12; H, 6.04; N, 6.88. Found: C, 53.07; H, 5.66; N, 6.73. 42

470.5 (+) 7.43 (m, 1 H), 7.27 (m, 3H), 7.08 (m, 2H), 6.70 (m, 1H), 4.67(m, 1 H), 4.21 (m, 2H), 3.02 (m, 2H), 1.23 (d, J = 6.0 Hz, 6 H). Anal.Calcd. for (C18H2ON3O6PS + 1.0 H2O): C, 44.35 H, 4.55; N, 8.62. Found:C, 44.56; H, 4.41; N, 8.27. 43

434.6 (+) 1.28 (d, 6H, J = 6 Hz), 1.32-1.36 (m, 2H), 1.53-1.58 (m, 2H),1.61 (d, 3H, J = 15 Hz), 1.76-1.80 (m, 2H), 2.29-2.33 (m, 1H), 3.91 (d,2H, J = 7 Hz), 4.71-4.74 (m, 1H), 6.68 (dd, 1H, J = 5, 3 Hz), 7.20- 7.22(m, 2H), 8.79 (s, 1H), 9.54 (s, 1H), 11.35 (s, 1H). Anal. (Calcd. forC₂₁H₂₈N₃O₅P + 1.1 HBr): C, 48.28; H, 5.61; N, 8.04, Found: C, 48.55; H,5.81: N, 7.76. 44

563.4 (+) 8.32 (d, J = 13 Hz, 1H), 7.96 (dd, J = 7, 2 Hz, 2 H), 7.78 (m,2H), 7.61 (s, 1 H), 7.44 (d, J = 2 Hz, 1 H), 7.27 (dd, J = 7, 2 Hz, 2H), 7.01 (t, J = 2 Hz, 1 H), 4.79 (m, 1 H), 3.22 (s, 3 H), 1.32 (d, J =6 Hz, 6 H). Anal. Calcd. for (C₂₄H₂₃N₂O₈PS₂ + 1.0 H₂O): C, 49.65; H,4.34: N, 4.83. Found: C, 49.78; H, 4.62; N, 4.57, 45

564.4 (+) 8.70 (dd, J = 6. 2 Hz, 1 H), 8.24 (dd, J = 13, 2 Hz, 1 H),7.96 (dd, J = 7, 2 Hz, 2H), 7.62 (m, 1 H), 7.45 (m, 1 H), 7.28 (dd, J =7, 2 Hz, 2 H), 7.02 (t, J = 2 Hz, 1 H), 4.80 (m, 1 H), 3.22 (s, 3 H),1.32 (d, J = 6 Hz, 6 H). Anal. Calcd. for (C₂₃H₂₂N₃O₈PS₂ + 0.3 H₂O): C,48.55; H, 4.00; N, 7.39. Found: C. 48.44; H, 3.96; N, 7.28. 46

564.4 (+) 8.19 (dd, J = 9, 5 Hz, 1 H), 7.94 (m, 3 H), 7.63 (d, J = 1 Hz,1H), 7.45 (m, 1 H), 7.28 (dd, J = 7, 2 Hz, 2 H), 7.03 (t, J = 2 Hz, 1H), 4.80 (m, 1 H), 3.23 (s, 3 H), 1.32 (d, J = 6 Hz, 6 H), Anal. Calcd.for (C₂₃H₂₂N₃O₈PS₂ +1.2 H₂O): C, 47.21; H. 4.20; N, 7.18. Found: C,47.28; H, 4.60; N, 6.89, 47

590.4 (+) 8.05 (m, 2H), 7.94 (d, J = 5.7 Hz. 2 H), 7.80 (m, 2H), 7.59(s, 1H), 7.42 (s, 1H), 7.25 (d, J = 9.0 Hz, 2H), 7.01 (m, 1H), 4.76 (m,1 H), 3.20 (s, 3H), 1.30 (d, J = 5.7 Hz, 6 H). Anal Calcd for(C25H24N3O8PS2 + 1.5 H2O): C, 48.70 H, 4.41; N, 6.81. Found: C, 48.67;H, 4.46; N, 6.72. 48

596.6 (+) 7.94 (m, 2H) 7.72 (m, 1H), 7.58 (d, J = 1.8 Hz, 1 H), 7.42 (m,3H), 7.25 (m, 2H), 7.01 (m, 1H), 4.77 (m, 1 H), 3.15 (s, 3H), 1.30 (d, J= 6.0 Hz, 6 H). Anal Calcd for (C23H22N3O8PS3): C, 46.38 H, 3.72; N,7.05. Found: C, 46.41; H, 3.71; N, 6.04. 49

469.3 (+) 7.72 (d, J = 5 Hz, 1 H), 7.35 (dd, J = 5, 2 Hz, 1 H), 7.28 (m,1 H), 7.25 (m, 1 H), 6.95-6.98 (m, 1 H), 6.70 (m, 1 H), 5.74 (m, 1 H),4.67- 4.75 (m, 1 H), 4.25 (t, J = 6 Hz, 2 H), 3.26 (t, J = 6 Hz, 2H),1.27 (d, J = 6 Hz, 6 H). Anal. Calcd. for (C20H23N2O5PS2 + 0.5 HBr): C,47.38; H, 4.67; N, 5.53. Found: C, 47.65; H, 4.47; N, 5.28. 50

505.3 (+) 7.75 (d, J = 5 Hz, 1 H), 7.25-7.32 (m, 5 H), 7.28 (m, 1 H),7.20-7.24 (m, 2 H), 6.70 (m, 1 H), 5.13 (m, 1 H), 4.81-4.87 (m, 1 H),3.74-3.93 (m, 4 H), 2.98-3.04 (m, 1 H), 2.86-2.93 (m, 1 H), 2.19-2.28(m, 1 H), 1.92-2.02 (m, 1 H), 1.26 (d, J = 6 Hz, 3 H), Anal. Calcd. far(C23H25N2O7PS + 1.4 H2O): C, 52.15: H, 5.29; N, 5.29. Found: C, 52.01:H, 5.35; N, 4.90 51

393.3 (+) 11.02 (s, 1 H), 8.62 (d, J = 3.0 Hz, 1 H), 8.27 (d, J = 6.0Hz, 1 H), 8.11 (t, J = 6.0 Hz, 1 H), 7.15 (s, 2 H), 6.61 (s, 1 H), 4.68(m, 2 H), 1.57 (d, J = 30 Hz, 3 H), 1.22 (s, 12 H). Anal. Calcd. for(C19H25N2O5P + 0.6 CH3COOH): C, 56.63; H, 6.45; N, 6.54. Found: C,56.55; H, 6.12; N, 6.48. 52

489.1 (+) 1.56 (d, 3H, J = 14 Hz), 5.19 (s, 4H), 6.88-6.90 (m, 2H),7.31-7.48 (m, 11H), 8.12-8.16 (m, 1H), 8.29 (d, 1H, J = 8 Hz), 8.67 (d,1H, J = 4 Hz), 11.07 (s, 1H), Anal. Calcd, for (C₂₇H₂₅N₂O₅P + 1.0 H20 +0.2 AcOH): C, 63.47; H, 5.40; N, 5.40. Found: C, 63.70; H, 5.40; N,5.25. 53

462.1 (+) δ 1.28 (d, 6H, J = 6 Hz), 1.68 (d, 3H, J = 15 Hz), 3.07 (t,2H, J = 7 Hz), 4.27 (t, 2H, J = 7 Hz), 4.69- 4.77 (m, 1H,), 6.72 (t, 1H,J = 2 Hz), 7.13 (dd, 1H, J = 5, 1 Hz), 7.24 (d, 2H, J = 12 Hz),7.33-7.34 (m, 1H), 7.49 (dd, 1H, J = 5, 3 Hz), 8.07 (br s, 1H), 8.47 (brs, 1H), 11.63 (br s, 1H). Anal. Calcd. for (C₂₁H₂₄N₃O₅PS + 1.0 H₂O + 0.3AcOH): C, 52.15; H, 5.51; N, 8.45. Found: C, 52.27; H, 5.22; N, 8.01. 54

464.0 (+) 1.28 (d, 6H, J = 6 Hz), 3.07 (t, 2H, J = 7 Hz), 4.26 (t, 2H, J= 7 Hz), 4.71-4.75 (m, 1H), 6.71-6.72 (m, 1H), 7.12-7.14 (m, 1H),7.21-7.25 (m. 2H), 7.33 (d, 1H, J = 2 Hz), 7.47-7.50 (m, 1H), 8.70 (s,1H), 9.54 (s, 1H), 11.31 (s, 1H). Anal. Calcd. for C₂₀H₂₂N₃O₆PS: C,51.83; H, 4.78; N, 9.07. Found: C, 51.78: H. 4.69: N, 8.98.

Examples 55-143

The following examples were prepared in a similar manner to Example 3from the appropriate intermediates with modifications evident to anindividual skilled in the art:

Mass Spect. 1H NMR δ (DMSO-d₆) & Example Structure (Mode) ElementalAnalysis 55

449.0 (+) 7.71 (dd, J = 12, 8 Hz, 2 H), 7.49 (m, 1 H), 7.26 (dd, J = 2,1 H), 7.21 (d, J = 1 Hz, 1H) 7.12 (dd, J = 8, 3 Hz, 2 H), 6.85 (m, 1 H),4.71-4.79 (m, 1H), 2.36 (d, J = 1 Hz, 3 H), 1.30 (d, J = 6 Hz, 6H) Anal.Calcd, for C20H21N2O6PS: C, 53.57; H, 4.72; N, 6.25, Found: C, 53.47; H,4.48; N, 6.16. 56

449.0 (+) 7.71 (dd, J = 12, 9 Hz, 2 H), 7.50 (m, 1 H), 7.26 (dd, J = 2,1 Hz, 1 H), 7.13 (dd, J = 9, 3 Hz, 2 H), 6.85 (m, 1 H), 6.82 (d, J = 1Hz, 1 H), 4.71-4.79 (m, 1 H), 2.30 (d, J = 1 Hz, 3 H), 1.30 (d, J = 6Hz, 6 H). Anal. Calcd. for (C20H21N2O6PS + 0.11 HBr): C, 52.53; H, 4.65;N, 6.13, Found: C, 52.77; H, 4.25; N, 6.41. 57

453.1 (+) 7.69 (dd, J = 12, 8 Hz, 2 H), 7.45 (m, 1 H), 7.38 (d, J = 3Hz, 1 H), 7.25 (m, 1 H). 7.07 (dd, J = 8, 3 Hz, 2 H), 6.83 (m, 1 H),4.69-4.77 (m, 1 H). 1.29 (d, J = 6 Hz, 6 H). Anal. Calcd. for(C19H18FN2O6PS + 0.5 HCl): C, 48.49; H, 3.96; N, 5.95. Found: C, 48.40;H, 4.09; N, 6.08. 58

469.1 (+) 7.77 (dd, J = 13, 1 Hz, 1 H), 7.64 (ddd, J = 12, 8, 2 Hz, 1H), 7.55 (d, J = 4 Hz, 1 H), 7.50 (m, 1 H), 7.28 (d, J = 3 Hz, 1 H),7.23 (d, J = 3 Hz, 1 H), 7.20(m, 1H), 6.85 (m, 1 H), 4.72-4.80 (m, 1 H),1.30 (d, J = 6 Hz, 6 H). Anal. Calcd. for (C19H18ClN2O6PS + 0.3 HCl +0.1 NH4Cl): C, 47.04: H, 3.98; N, 6.06. Found: C, 46.84; H, 3.62; N,5.90. 59

503.4 (+) 7.73 (dd, J = 12, 2 Hz, 1 H), 7.58-7.62 (m, 1 H),7.56 (s, 1H), 7.44 (m, 1 H), 7.14 (m 1 H), 7.11 (d, J = 3 Hz, 1 H), 6.74 (m, 1 H.4.68-4.76 (m, 1 H), 1.28 (d, J = 6 Hz, 6 H). Anal. Calcd. for(C19H17Cl2N2O6PS + 0.2 H2O + 0.1 acetone): C, 42.52; H, 3.99; N, 5.14.Found: C, 42.36; H, 3.63; N, 5.08. 60

547.4, 549.1, 551.4 (+) 7.89-7.94 (m, 1 H), 7.63-7.70 (m, 1 H), 7.59 (m,1 H), 7.49 1 (m, 1 H), 7.16-7.19 (m, 2 H), 6.85 (m, 1 H), 4.70-4.78 (m,1 H), 1.28 (d, J = 6 Hz, 6 H). Anal. Calcd. for (C19H17BrClN2O6PS + 0.2HBr + 0.05 acetone): C, 40.58; H, 3.11; N, 4.94. Found: C, 40.40 H,3.23; N, 4.87. 61

513.4, 515.4 (+) 7.92 (dd, J = 13, 2 Hz, 1 H), 7.68 (ddd, J = 12, 8, 2Hz, 1 H),7.54 (d, J = 4 Hz, 1 H), 7.51 (m, 1 H), 7.28 (d, J = 4 Hz, 1H), 7.17-7.21 (m, 2 H), 6.84 (m, 1 H), 4.68-4.76 (m, 1 1 H), 1.28 (d, J= 6 Hz, 6 H). Anal. Calcd. for (C19H18BrN2O6PS + 0.05 HBr): C, 44.11; H,3.52; N, 5.41. Found: C, 44.08; H, 3.25; N, 5.25. 62

531.1, 533.1 (+) 7.91 (dd, J = 13, 2 Hz, 1 H), 7.67 (ddd, J = 12, 8. 2Hz, 1 H), 7.47 (m, 1 H), 7.38 (d, J = 2 Hz, 1 H), 7.17 (dd, J = 8, 3 Hz,1 H), 7.14 (dd, J = 2, 1 Hz, 1 H), 6.84 (m, 1 H), 4.70- 4.78 (m, 1 H),1.28 (d, J = 6 Hz, 6 H). Anal. Calcd. for C19H17BrFN2O6P: C, 42.95; H,3.23; N, 5.27. Found: C, 42.83; H, 2.98; N, 5.16. 63

483.0 (+) 7.00-7.01 (m, 1H), 7.12 (dd, 2H, J = 9, 3 Hz), 7.29 (d, 1H, J= 4 Hz), 7.33-7.37 (m, 2H), 7.41 (t, 2H, J = 8 Hz), 7.47- 7.48 (m, 2H),7.56 (dd, 1H, J = 4, 1 Hz), 7.65 (s, 1H), 7.68- 7.73 (m, 2H). Anal.Calcd. for C₂₃H₁₉N₂O₆PS + 0.1 HBr + 0.1 H₂O: C, 56.11; H, 3.95; N, 5.69.Found: C, 56.07; H, 3.66; N. 5.58. 64

429.4 (+) 10.94 (s, 1H), 8.44 (d, J = 3.3 Hz, 1H), 8.19 (d, J = 6.4 Hz,1H), 7.90 (m, 1 H), 7.77 (m, 2H), 7.50 (s, 1H), 7.21 (m, 4H), 6.89 (s,1H), 4.83 (m, 1 H), 1.36 (d, J = 5.7 Hz, 6H). Anal. Calcd. for(C21H21N2O6P + 0.15 HBr + 0.4 H2O): C, 56.34 H, 4.94; N, 6.26. Found: C,56.74; H, 4.92; N, 5.81 65

497.4 (+) 11.31 (s, 1H), 8.76 (s, 1H), 8.34 (d, J = 9.0 Hz, 1H), 8.22(m, 1H), 7.69 (m, 2 H), 7.43 (d, J = 1.8 Hz, 1H), 7.21 (d, J = 1.8 Hz,1H), 7.11 (d, J = 6.6 , Hz, 2H), 6.83 (m, 1H), 4.75 (m, 1 H), 1.28 (d, J= 6.0 Hz, 6H). Anal. Calcd. for (C22H20F3N2O6P + 0.7 H2O): C, 51.91 H,4.24; N, 5.50. Found: C. 51.84; H, 4.13; N, 5.42. 66

434.6 (+) 1.29 (d, 6H, J = 6 Hz). 4.71- 4.74 (m, 1H), 6.77 (s, 1H), 7.01(d, 2H, J = 8 Hz), 7.26- 7.29 (m, 2H), 7.42 (t, 1H, J = 8 Hz), 7.49 (s,1H), 7.65-7.72 (m, 3H), 7.95 (d, 1H, J = 8 Hz); Anal. Calcd. forC₂₁H₂₈N₃O₅P + 1.1 HBr: C, 48.28; H, 5.61; N, 8.04. Found: C, 48.55; H,5.81; N, 7.76. 67

463.5 (+) 7.69 (m, 2 H), 7.47 (s, 1H), 7.23 (s, 1H), 7.21 (m, 2H), 6.82(m, 1H), 4.73 (m, 1 H), 2.23 (s, 3H), 2.17 (s. 3H), 1.28 (d, J = 6.0 Hz,6H). Anal. Calcd. for (C21H23N2O6PS): C, 54.54 H, 5.01; N, 6.06. Found:C, 54.28; H, 4.82; N, 5.87. 68

476.5 (+) 7.69 (m, 2 H), 7.48 (m, 1H), 7.26 (m, 1H), 7.10 (m, 2H), 6.86(m, 1H), 4.73 (m, 1 H), 2.39 (m, 1H), 1.28 (d. J = 6.0 Hz, 6H), 1.13 (m,2H), 0.98 (m, 2H). Anal. Calcd. for (C21H22N3O6PS + 0.8 MeOH): C, 52.25H, 5.07; N, 8.39. Found: C, 52.15; H, 4.94; N, 8.58. 69

464.4 (+) 7.27 (m, 2 H), 7.60 (m, 1H), 7.38 (m, 1H), 7.18 (m, 2H), 6.95(m, 1H). 4.81 (m, 1 H), 2.88 (m, 2H), 1.29 (m. 9H). Anal. Calcd. for(C20H22N3O6PS + 0.1 HBr): C, 50.94 H, 4.72; N, 8.91. Found: C, 50.96; H,4.37; N, 8.73. 70

450.4 (+) 7.78 (m, 2 H), 7.60 (s, 1H), 7.37 (s, 1H), 7.20 (d, J = 7.5Hz, 2H), 6.98 (s, 1H), 4.82 (m, 1 H), 2.5 (s, 3H), 1.37 (d, J = 6.3 Hz,6H). Anal. Calcd. for (C19H20N3O6PS + 0.1 HBr + 0.23 H2O): C, 49.43 H,4.49; N, 9.10. Found: C, 49.83; H, 4.53; N, 8.68. 71

469.8 (+) 7.78 (m, 2 H), 7.67 (s, 1H), 7.56 (s, 1H), 7.19 (m, 2H), 6.94(s, 1H), 4.81 (m, 1 H). 1.36 (d, J = 5.7 Hz. 6H), Anal. Calcd. for(C19H18ClN2O6PS): C, 48.67 H, 3.87; N, 5.97. Found: C, 48.44; H, 3.61;N, 5.78. 72

478.5 (+) 7.70 (m, 2 H), 7.53 (m, 1H), 7.30 (m, 1H), 7.12 (m, 2H), 6.88(m, 1H), 4.74 (m, 1 H), 3.10 (m, 1H), 1.28 (m, 12H). LC-MS m/z = 478.5[C21H24N3O6PS + H]⁺; Anal. Calcd. for (C21H24N3O6PS + 0.9 TFA): C, 47.21H. 4.33; N, 7.24. Found: C, 47.21; H, 4.55; N, 7.20. 73

475.5 (+) 7.68 (m, 2H), 7.46 (s, 1H), 7.22 (s, 1H), 7.10 (m, 2H), 6.81(m, 1H), 4.72 (m, 1 H), 2.81(m, 2H), 2.67 (m, 2H), 2.35 (m, 2H), 1.27(d, J = 5.7 Hz, 6H). Anal. Calcd. for (C22H23N2O6PS + 0.3 HBr): C,52.98; H, 4.71; N, 5.62 Found: C, 53.20; H, 4.39; N, 5.79 74

467.4 (+) 7.76 (m, 2 H), 7.60 (m, 2H), 7.46 (d, J = 2.4 Hz, 1H), 7.38(s, 1H), 7.32 (s, 1H), 6.85 (s, 1H), 5.28 (s, 2H), 4.78 (m, 1 H), 1.34(d, J = 6.0 Hz, 6H). Anal. Calcd. for (C20H20FN2O6PS + 0.1 HBr): C,50.62 H. 4.27; N. 5.90, Found: C, 50.72; H, 4.40; N, 5.67. 75

483.9 (+) 7.71 (m, 2 H), 7.63 (s, 1H), 7.56 (m, 2H). 7.35 (s, 1H), 7.29(s, 1H), 6.81 (s, 1H), 5.24 (s, 2H), 4.73 (m, 1 H), 1.29 (d, J = 6.0 Hz,6H). Anal. Calcd. for (C20H20ClN2O6PS): C, 49.75 H, 4.17; N, 5.80.Found: C, 49.48; H, 4.13; N. 5.81. 76

436.4 (+) 9.21 (s, 1H), 7.70 (m, 2 H), 7.52 (m, 1H), 7.28 (m, 1H), 7.12(m, 2H), 6.88 (m, 1H), 4.74 (m, 1 H), 1.29 (d, J = 6.3 Hz, 6H). Anal.Calcd. for (C18H18N3O6PS): C, 48.75 H, 4.11; N, 9.47. Found: C, 48.91;H, 4.02; N, 9.35. 77

457.4 (+) 7.41 (s, 1 H), 7.40 (s, 1H), 7.26 (s, 1H), 6.85 (m, 2H), 6.66(m, 1H), 5.17 (s, 2H), 4.73 (m, 1 H), 1.29 (d, J = 5.7 Hz, 6H). Anal.Calcd. for (C18H18FN2O7PS + 0.15 HBr): C, 46.14 H, 3.90; N, 5.98. Found:C, 46.17; H, 4.13; N, 5.79. 78

436.4 (+) 7.72 (m, 2 H), 7.57 (m, 1H), 7.34 (m, 1H), 7.14 (m, 2H), 6.93(m, 1H), 4.77 (m, 1 H), 1.32 (d, J = 6.0 Hz, 6H). Anal. Calcd. for(C18H18N3O6PS + 0.2 HBr): C, 47.88 H, 4.06; N, 9.31. Found: C, 8.00; H,3.79; N, 9.43. 79

528 .3 (+) 7.68 (m. 3 H), 7.52 (m, 2H), 7.32 (m, 1H), 7.26 (s, 1H), 6.78(m, 1H), 5.21 (s, 2H), 4.70 (m, 1 H), 1.26 (d, J = 3.6 Hz, 6H). Anal.Calcd. for (C20H20BrN2O6PS): C, 45.55 H, 3.82; N, 5.31. Found: C, 45.73;H, 3.66; N, 5.18. 80

514.3 (+) δ 7.70 (m, 2 H), 7.65 (s, 1H), 7.49 (m, 1H), 7.26 (m, 1H),7.12 (m, 2H), 6.87 (m, 1H), 4.74 (m, 1 H), 1.29 (d, J = 3.6 Hz, 6H).Anal. Calcd, for (C19H18BrN2O6PS); C, 44.46 H, 3.53; N, 5.46. Found: C,44.45; H, 3.66; N, 5.18. 81

483.9 (+) 7.66 (m, 2 H), 7.44 (s; 1H), 7.21 (s, 1H), 7.07 (m, 2H), 6.81(m, 1H), 4.69 (m, 1 H), 2.20 (s, 3H), 1.24 (d, J = 6.0 Hz, 6H). Anal.Calcd. for (C20H20ClN2O6PS): C, 49.75 H, 4.17; N, 5.80. Found: C. 50.03;H, 3.92; N, 5.64. 82

487.4 (+) 1.30 (d, 6H, J = 6 Hz), 4.73- 4.78 (m, 1H), 6.89-7.01 (m, 3H),7.33 (t, 1H, J = 2 Hz), 7.52 (t, 1H, J = 2 Hz), 7.61 (s, 1H), 7.65-7.75(m, 1H). Anal. Calcd, for C₁₉H₁₇ClFN₂O₆PS: C, 46.88; H, 3.52; N, 5.75.Found: C. 47.04; H, 2.86; N, 5.58. 83

489.4 (+) 7.61 (s, 1 H), 7.30 (m, 4H), 6.80 (m, 1H), 5.39 (s, 2H), 4.72(m, 1 H), 1.28 (d, J = 6.0 Hz, 6H). Anal Calcd for (C18H18ClN2O6PS2); C,44.22 H, 3.71; N, 5.73. Found: C, 44.16; H, 3.79; N, 5.61. 84

473.4 (+) 7.39 (d, J = 2.7 Hz, 1 H), 7.32 (m, 2H), 7.23 (m, 2H), 6.79(m, 1H), 5.39 (s, 2H), 4.71 (m, 1 H), 1.27 (d, J = 6.3 Hz, 6H), AnalCalcd for (C18H18FN2O6PS2): C, 45.76 H, 3.84; N, 5.93. Found: C. 45.67;H, 3.93; N, 6.12, 85

455.1 (+) 7.59 (d, J = 3.6 Hz, 1 H), 7.34 (m, 5H), 6.82 (s, 1H), 5.43(s, 2H), 4.76 (m, 1 H), 1.31 (d, J = 5.7 Hz, 6H). Anal Calcd for(C18H19N2O6PS2 + 1.0 H2O): C, 45.76, 4.48; N, 5.93. Found: C, 46.12; H,4.40; N, 5.54. 86

471.4 (+) 8.63 (d, J = 6.0 Hz, 2H), 7.58 (d, J = 1.2 Hz, 1 H), 7.50 (m,1H), 7.46 (m, 1H), 7.06 (m, 1H), 4.72 (m, 1 H), 1.28 (d, J = 6.3 Hz,6H), Anal Calcd for (C17H16ClN4O6PS + 0.5 NH3 + 1.2 H2O): C, 40.76; H,4.00; N, 12.58. Found: C, 40.59; H, 4.22; N, 12.73. 87

504.6 (+) 8.50 (m, 1 H), 8.14 (dd, J = 8, 1 Hz, 1 H), 7.65-7.75 (m, 1H), 7.56 (m, 1 H), 7.51 (dd, J = 8, 5 Hz, 1 H), 7.36 (m, 1H) 6.91-7.02(m, 3 H), 4.72-4.80 (m, 1 H), 1.29 (d, J = 6 Hz, 6 H). Anal. Calcd, for(C22H19FN3O6PS + 2.0 HBr + 2.0 H2O): C. 37.68; H, 3.59; N, 5.99. Found:C, 37.65; H, 3.64; N, 5.59. 88

486.6 (+) 8.48 (dd, J = 5, 1 Hz, 1H), 8.12 (dd, J = 8, 1 Hz, 1H), 7.10(dd, J = 12, 9 Hz, 2H), 7.54 (m, 1 H), 7.50 (dd, J = 8, 5 Hz, 1H), 7.31(m, 1 H), 7.14(dd, J = 9, 3 Hz, 2H), 6.89 (m, 1H), 4.75-4.81 (m, 1 H),1.32 (d, J = 6 Hz, 6 H). Anal. Calcd. for (C20H20N3O6PS + 0.5 H2O): C,53.44; H, 4.28; N, 8.50. Found: C. 53.55; H, 4.07; N, 8.43. 89

483.1 (+) ¹H NMR (300 MHz, DMSO- d₆) δ 1.29 (d, 6H), 4.72-4.77 (m, 1H),6.84 (t, 1H), 6.89 (d, 1H), 6.95 (s, 1H), 7.24 (t, 1H), 7.47 (s, 1H),7.60 (s, 1H), 7.76 (dd, 1H); Anal. Calcd. for (C20H20ClN2O6PS + 0.6H2O): C, 48.66; H, 4.33; N, 5.67. Found: C. 48.98; H, 4.03; N, 5.39. 90

470.4 (+) ¹H NMR (300 MHz, DMSO- d₆) δ 1.31 (d, 6H), 4.72-4.78 (m, 1H),6.99 (t, 1H), 7.32 (t, 1H), 7.50-7.61 (m, 2H), 7.61 (s, 1H), 7.83 (dd,1H), 8.58 (d, 1H); Anal. Calcd. for (C₁₈H₁₇ClN₃O₆PS): C, 46.02; H, 3.65;N, 8.94. Found: C, 45.75; H, 3.82; N, 8.72. 91

470.4 (+) ¹H NMR (300 MHz, DMSO- d₆) δ 1.30 (d, 6H), 4.72-4.77 (m, 1H),7.02 (t, 1H), 7.15 (dd, 1H), 7.42 (s, 1H), 7.54 (S. 1H), 7.61 (s, 1H),8.02-8.10 (m, 1H), 8.38 (dd, 1H); Anal. Calcd. for (C₁₈H₁₇ClN₃O₆PS), C,45.15; H, 3.79; N, 8.78. Found: C, 45.46; H, 3.52; N, 8.73. 92

484.1 (+) ¹H NMR (300 MHz, DMSO- (d₆) δ 1.30 (d, 6H), 2.53 (s, 3H),4.72-4.77 (m, 1H), 6.98- 7.01 (m, 2H), 7.39 (s, 1H), 7.53 (s. 1H), 7.61(s, 1H), 8.35 (d, 1H), Anal. Calcd. for (C₁₉H₁₉ClN₃O₆PS + 1.0 H2O): C,45.47; H, 4.22; N, 8.37. Found: C, 45.63; H, 3.89; N. 7.97. 93

494.4 (+) ¹H NMR (300 MHz, DMSO- (d₆) δ 1.30 (d, 6H), 4.75-4.80 (m, 1H),7.12-7.13 (m, 2H), 7.42 (s, 1H), 7.57 (s, 1H), 7.61 (s, 1H), 7.88-7.95(m, 1H), 8.04 (d, 1H); Anal. Calcd. for (C₂₀H₁₇ClN₃O₆PS + 1.1 HBr): C,41.21, H, 3.13, N, 7.21. Found: C, 41.29; H, 3.05; N, 6.89. 94

499.6 (+) ¹H NMR (300 MHz, DMSO- (d₆) δ 1.29-1.31 (m, 6H), 3.77 (s, 3H).4.71-4.79 (m, 1H), 6.59 (d, 1H), 6.80 (d, 1H), 6.87 (d, 1H), 7.29 (s,1H), 7.50 (s, 1H), 7.61 (d, 1H), 7.64-7.69 (m, 2H); Anal. Calcd. for(C₂₀H₂₀ClN₂O₇PS + 0.9 H₂O): C, 46.64; H, 4.27; N, 5.44, Found: C, 45.76;H, 4.27; N, 5.27. 95

471.4 (+) ¹H NMR (300 MHz, DMSO- d₆) δ 1.30 (d, 6H), 4.72-4.77 (m, 1H),7.14 (t, 1H), 7.50 (s, 1H), 7.57 (d, 1H), 7.62 (d, 1H), 8.46 (s, 1H),8.72 (d, 1H); Anal. Calcd. for (C₁₇H₁₆ClN₄O₆PS): C, 43.37; H, 3.43; N,11.90. Found: C, 43.62; H, 3.47; N, 11.61. 96

483.1 (+) 7.61 (s, 1 H), 7.43 (m, 1H), 7.28 (m, 1H), 7.08 (d, J = 7.5Hz, 1H), 6.99 (d, J = 1.5 Hz, 1H), 6.91 (d, J = 8.0 Hz, 1H), 6.76 (m,1H), 4.72 (m, 1 H), 2.98 (d, J = 21.5 Hz, 2H) 1.28 (d, J = 6.0 Hz, 6H).Anal Calcd for (C20H20ClN2O6PS + 0.2 H₂O): C, 49.38 H, 4.23; N, 5.76.Found: C, 49.25; H, 4.02; N, 5.50. 97

449.4 (+) 7.74 (d, J = 4.0 Hz, 1 H), 7.52 (d, J = 4.5 Hz, 1H), 7.37 (m,1H), 7.33 (d, J = 2.0 Hz, 1H), 7.16 (m, 3H), 6.99 (d, J = 7.5 Hz, 1H),6.92 (m, 1H), 4.70 (m, 1 H), 3.18 (d, J = 21.5 Hz, 2H) 1.36 (d, J = 6.0Hz, 6H). Anal Calcd for (C20H21N2O6PS + 1.5 HBr + 0.4 H₂O): C, 41.63 H,4.07; N, 4.85. Found: C, 41.70; H, 4.29; N, 4.65. 98

547.6 (+) 800 (d, J = 4.0 Hz, 2 H), 7.57 (m, 5H), 7.51 (m, 2H), 7.31 (m,3H), 7.08 (s, 1H), 3.14 (s, 3H). Anal Calcd for (C23H19N2O8PS2 + 1.3HBr + 0.3 H₂O): C, 42.04 H. 3.21; N, 4.26. Found: C, 41.86; H, 3.49; N.4.00. 99

519.6 (+) 12.68 (bs, 1 H), 7.73 (m, 2 H), 7.54 (m, 2 H), 7.36 (t, J = 2Hz, 1 H), 7.28 (d, J = 4 Hz, 1H), 7.16 (m, 2 H), 6.93 (t, J = 4 Hz, 1H), 4.76 (m, 1 H), 4.55 (m, 2 H), 1.29 (m, 12 H), 1.18 (d, J = 6 Hz, 6H). Anal. Calcd. for (C₂₅H₃₁N₂O₆PS): C, 57.90: H, 6.03; N, 5.40. Found:C, 57.73; H, 5.99; N, 5.37. 100

465.6 (+) 7.69 (t, J = 9 Hz, 2 H), 7.44 (s, 1 H), 7.29 (d, J = 2 Hz,1H), 7.04 (dd, J = 7.1 Hz, 2 H), 6.78 (s, 1 H), 4.70 (m, 1 H), 1.50 (m,2 H), 1.25 (m, 6 H) 0.86 (m, 3 H). 101

475.6 (+) 7.72 (t, J = 10 Hz, 2 H), 7.55 (d, J = 4 Hz, 1 H), 7.50 (s,1H), 7.28 (dd, J = 8, 4 Hz, 2 H), 7.10 (d, J = 8 Hz, 2 H), 6.83 (s, 1H), 4.74 (m, 1 H), 1.81 (m, 1 H), 1.60 (m, 2 H), 1.28 (m, 6 H), 0.90 (d,J = 6 Hz, 6 H). Anal. Calc. for (C₂₃H₂₇N₂O₅PS): C, 58.22; H, 5.74; N,5.90. Found: C, 58.01; H, 5.58; N, 5.75. 102

467.4 (+) 7.69 (m, 1 H), 7.51 (d, 1= 2 Hz, 1 H), 7.32 (dd, J = 3.2 Hz,1H), 7.22 (d, J = 2 Hz, 1 H), 6.98 (m, 1 H), 6.90 (m, 2 H), 4.75 (m, 1H), 2.36 (d, 1= 1 Hz, 3 H), 1.30 (d, J = 6 Hz, 6 H). Anal. Calcd. for(C₂₀H₂₀FN₂O₆PS): C, 51.50; H, 4.32; N, 6.01. Found: C, 51.25; H, 4.28;N, 5.71. 103

471.6 (+) 7.69 (m, 1 H), 7.51 (t, J = 2 Hz, 1 H), 7.39 (d, J = 2 Hz,1H), 7.31 (dd, J = 3, 2 Hz, 1 H), 6.92 (m, 3 H), 4.76 (m, 1 H), 1.30 (d,J = 6 Hz, 6 H). Anal. Calcd. for (C₁₉H₁₇F₂N₂O₆PS): C, 47.78; H, 3.76; N,5.87. Found C, 47.77; H, 3.65; N, 6.04. 104

447.9 (+) 7.73 (m, 2 H), 7.56 (s, 1 H), 7.53 (dd, J = 3, 1 Hz, 1H), 7.31(m, 2 H), 7.15 (dd, J = 9, 2 Hz, 2 H), 6.88 (t, J = 2 Hz, 1 H). 4.76 (m,1 H), 1.74 (m, 2 H), 1.30 (d, J = 6 Hz, 6 H), 0.95 (m, 3 H). Anal.Calcd, for (C21H23N2O5PS +0.5 HCl): C, 54.28; H, 5.10; N. 6.03. Found:C, 54.03; H, 4.76; N, 5.89. 105

461.6 (+) 7.73 (m, 2H), 7.51 (t, J = 2 Hz, 1 H), 7.29 (t, J = 1 Hz, 1H),7.28 (d, J = 1 Hz, 1 H), 7.15 (m, 2 H), 6.87 (t, J = 3 Hz, 1 H), 4.76(m, 1 H), 2.36 (s, 3 H). 1.74 (m, 2 H), 1.30 (d, J = 6 Hz, 6 H), 0.95(m, 3 H). Anal. Calcd, for (C₂₂H₂₅N₂O₅PS +0.7 HCl) C, 54.37; H, 5.33; N,5.76. Found: C, 54.65; H, 4.91; N, 5.71. 106

489.6 (+) 7.74 (t, J = 8 Hz, 2 H), 7.50 (s, 1 H), 7.28 (s, 1H), 7.22 (s,1 H), 7.13 (d, J = 7 Hz, 2 H) 6.85 (s, 1 H), 4.75 (m, 1 H), 2.36 (s, 3H), 1.83 (m, 1 H), 1.68 (m, 2 H), 1.30 (d, J = 6 Hz, 6 H), 0.92 (d, J=∂Hz, 6 H), Anal. Calcd. for (C₂₄H₂₉N₂O₅ +LPS): C, 59.01; H, 5.98; N,5.73, Found: C, 58.82; H, 5.91; N, 5.46, 107

483.1 (+) 7.79 (d, J = 13.2 Hz. 1H), 7.65 (m, 2H), 7.63 (s, 1H). 7.51(m, 1H), 7.36 (m, 1H), 7.29 (m, 1H), 6.82 (m, 1H), 5.23 (s, 2H), 4.74(m, 1 H), 1.29 (d, J = 6.0 Hz, 6H). Anal Calcd for (C20H20ClN2O6PS + 0.8H₂O): C, 48.31 H, 4.38; N, 5.63, Found: C, 48.41; H, 4.47; N, 5.33. 108

467.4 (+) 7.77 (d, J = 13.2 Hz, 1 H), 7.63 (m, 2H), 7.50 (m, 1H). 7.39(d, J = 2,4 Hz, 1H), 7.32 (m, 1H), 7.25 (m, 1H), 6.79 (m, 1H), 5.21 (s,2H), 4.71 (m, 1 H), 1.27 (d, J = 6.0 Hz, 6H). Anal Calcd for(C20H20FN2O6PS + 0.3 H₂O): C, 50.91 H, 4.40; N, 5.94, Found: C, 50.85;H, 4.39; N, 5.74. 109

449.4 (+) 7.78 (d, J = 13.2 Hz, 1 H), 7.53 (m, 4H), 7.36 (s, 1H), 7.28(m, 2H), 6.79 (m, 1H), 5.22 (s, 2H), 4.73 (m, 1 H), 1.29 (d, J = 6.0 Hz,6H). Anal Calcd for (C20H21N2O6PS): C, 53.57 H, 4.72; N, 6.25. Found: C,53.49; H, 4.76: N, 5.98. 110

487.4 (+) 7.59 (s, 1 H), 7.53 (d, J = 12.3 Hz, 1H), 7.48 (s, 2H), 7.27(m, 2H), 7.18 (s, 1H), 6.88 (s, 1H), 4.74 (m, 1 H), 1.28 (d, J +32 6.0Hz, 6H). Anal Calcd for (C19H17ClFN2O6PS): C, 46.88 H, 3.52; N, 5.75.Found: C, 46.83; H. 3.80; N, 5.53. 111

453.4 (+) δ 7.54 (m, 4H), 7.29 (m, 2H), 7.19 (s, 1H), 6.86 (s, 1H), 4.75(m, 1 H), 1.29 (d, J = 6.0 Hz, 6H). Anal Calcd for (C19H18FN2O6PS + 0.8H2O): C, 48.89 H, 4.23; N, 6.00, Found: C, 48.75; H, 4.05; N, 5.83. 112

469.4 (+) 7.59 (s, 1 H), 7.48 (m, 3H), 7.25 (m, 3H), 6.82 (s, 1H), 4.73(m, 1 H), 1.28 (d, J = 6.0 Hz, 6H). Anal Calcd for (C19H18ClN2O6PS + 0.2H2O): C, 48.30 H. 3.93; N. 5.93. Found: C, 48.51; H, 5.88; N, 4.29. 113

453.4 (+) 7.48 (m, 3H), 7.37 (m, 1 H), 7.23 (m, 3H), 6.81 (s, 1H), 4.73(m, 1 H), 1.28 (d, J = 6.0 Hz, 6H). Anal Calcd for (C19H18FN2O6PS + 0.6H2O): C, 49.27 H, 4.18; N, 6.05. Found: C, 49.73, H, 4.65; N, 6.14. 114

490.4 (+) 8.14 (s, 1 H), 7.63 (s, 1H), 7.37 (m, 1H), 7.31 (m, 1H), 6.84(m, 1H), 5.51 (s, 2H), 4.74 (m, 1 H), 1.30 (d, J = 6.0 Hz, 6H). AnalCalcd for (C17H17ClN3O6PS2 + 1.6 H2O): C, 39.36 H, 3.93; N, 8.10, Found:C, 42.70; H, 402; N, 7.65 115

474.6 (+) 8.11 (s, 1 H), 7.38 (d, J = 2.7 Hz), 7.32 (s, 1H), 7.26 (s,1H), 6.81 (m, 1H), 5.48 (s, 2H), 4.71 (m, 1 H), 1.27 (d, J = 6.3 Hz,6H), Anal Calcd for (C17H17FN3O6PS2): C, 43.13 H, 3.62; N, 8.88. Found:C, 42.89; H, 3.75; N, 8.48. 116

479.1 (+) 7.68-7.77 (m, 1 H), 7.55 (d, J = 4 Hz, 1H), 7.54 (m, 1 H), Hz,1 H), 7.02 (m, 1 H), 6.98 (m, 1 H), 6.95 (m, 1 H), 4.72- 4.80 (m, 1 H),1.90-2.04 (m, 1 H), 1.30 (d, J = 6 Hz, 6H), 1.00 (dd, J = 18, 7 Hz, 6H), Anal Calcd for (C22H24FN2O5PS + 0.9 H2O): C, 43.13 H, 3.62; N, 8.88.Found: C, 42.89; H, 3.75; N, 8.48. 117

512.4 (+) 7.60 (s, 1 H), 7.40 (m, 1 H), 7.31(dd, J = 14, 2 Hz, 1 H),7.24 (ddd, J = 12, 8, 2 Hz, 1 H), 7.09 (m, 1 H), 7.01 (dd, J = 8, 4 Hz,1 H), 6.66 (m, 1 H) 4.65-4.75 (m, 1 H), 2.73 (s, 3 H), 1.27 (d, J = 6Hz, 6 H). Anal. Calcd. for (C21H23ClN3O6PS + 0.1 HBr): C, 48.50; H,4.48; N, 8.08. Found: C, 48.60; H, 4.70; N, 8.08. 118

496.1 (+) 7.30-7.36 (m, 3 H), 7.24 (dd, J = 12, 9 Hz, 1 H), 7.09 (m, 1H), 6.96 (dd, J = 8, 4 Hz, 1 H), 6.61 (m, 1H), 4.65-4.72 (m, 1 H), 2.69(s, 3 H), 1.25(d, J = 6 Hz, 6H), Anal. Calcd. for (C21H231FN3O6PS + 0.1HBr + 0.1 NH4Br): C, 49.13; H, 4.61; N, 8.46. Found: C, 48.90; H, 4.76;N, 8.75. 119

471.4 (+) 4.65-4.68 (m, 1H), 4.74-4.78 (m, 2H), 4.83-4.84 (m, 1H),5.05-5.20 (m, 1H), 7.03 (d, 1H, J = 2 Hz), 7.16 (dd, 2H, J = 9.3 Hz),7.29 (d, 1H, J = 4 Hz), 7.63 (s, 1H), 7.56 (d, 1H, J = 4 Hz), 7.63 (s,1H), 7.72 (dd, 2H, J = 13, 8 Hz) Anal. Calcd. for (C₁₉H₁₇F₂N₂O₆PS + 0.7H₂O): C, 47.25; H, 3.84; N, 5.80. Found: C, 47.35; H, 3.52; N, 5.71. 120

433.4 (+) 1.27 (d, 6H, J = 6 Hz), 2.39 (s, 3H), 4.68-4.73 (m, 1H), 6.71(s, 1H), 6.75 (t, 1H, J = 2 Hz), 6.97 (d, 2H, J = 8 Hz), 7.15 (dd, 1H, J= 2, 1 Hz). 7.35 (dd, 1H, J = 4, 1 Hz), 7.58-7.74 (m, 2H). Anal. Calcd.for C₂₀H₂₁N₂O₇P + 0.5 HBr + 1.1 NH₃: C, 48.87; H, 5.09; N, 8.83. Found:C, 48.71; H, 5.02; N, 8.71 121

464.4 (+) 7.70 (m, 2 H), 7.50 (s, 1H), 7.27 (s, 1H), 7.11 (d, J = 7.5Hz, 2H), 6.87 (s, 1H), 4.74 (m, 1 H), 2.99 (m, 2H), 1.29 (m, 9H). Anal.Calcd. for (C20H22N3O6PS + 0.1 HBr + 0.2 H2O): C, 50.56 H, 4.77; N.8.84. Found: C, 50.91; H, 4.46; N, 8.45. 122

497.4 (+) 11.33 (s, 1H), 8.65 (d, J = 4.8 Hz, 1H), 8.48 (s, 1H), 7.70(m, 2 H), 7.52 (d, J = 5.1 Hz, 1H), 7.44 (s, 1H), 7.22 (m, 1H), 7.11 (m,2H), 6.84 (m, 1H), 4.75 (m, 1 H), 1.28 (d, J = 6.3 Hz, 6H). Anal. Calcd.for (C22H20F3N2O6P + 0.1 HBr): C, 52.38 H, 4.02; N, 5.55. Found: C,52.58; H, 3.83; N, 5.52, 123

447.4 (+) 11.02 (s, 1H), 8.09 (m, 1H), 8.00 (m, 1H), 7.70 (m, 2H), 7.41(m, 1H), 7.19 (m, 1H), 7.10 (d, J = 7.5 Hz, 2H), 6.90 (m, 1H), 6.81 (m,1H), 4.75 (m, 1 H), 1.28 (d, J = 6.0 Hz, 6H). Anal. Calcd, for(C21H20FN2O6P + 0.2 HBr): C, 54.53 H, 4.40; N, 6.06. Found: C, 54.74; H,4.35; N, 5.88. 124

450.4 (+) 7.70 (m, 2 H), 7.50 (m, 1H), 7.27 (m, 1H), 7.12 (m, 2H), 6.87(m, 1H), 4.74 (m, 1 H), 2.62 (s, 3H), 1.29 (d, J = 6.3 Hz, 6H). Anal.Calcd. for (C19H20N3O6PS): C, 50.78 H, 4.49; N, 9.35. Found: C, 50.56;H, 4.43; N, 9.23. 125

504 .4 (+) 7.71 (m, 2 H), 7.54 (m, 1 H), 7.31 (m, 1 H), 7.13 (m, 2 H).6.93 (m, 1 H), 4.75 (m, 1 H), 1.30 (d, J = 6 Hz, 6 H). Anal. Calcd. for(C19H17F3N3O6PS + 0.8 H2O): C, 44.07; H, 3.62; N, 8.12. Found: C, 44.38;H, 8.11. 126

492.4 (+) 7.70 (m, 2 H), 7.49 (m, 1 H), 7.27 (m, 1 H), 7.12 (m, 2 H),6.87 (m, 1 H), 4.73 (m, 1 H), 1.39 (s, 9 H), 1.28 (d, J = 6 Hz, 6 H).Anal. Calcd, for (C22H26N3O6PS + 1.0 MeOH): C, 52,77; H, 5.78; N, 8.03.Found: C, 53.00; H, 5.78; N, 7.65. 127

449.4 (+) 7.68 (m, 2 H), 7.52 (m, 3H), 7.33 (m, 1H), 7.26 (m, 2H), 6.75(s, 1H), 5.21 (s 2H), 4.70 (m, 1 H), 1.26 (d, J = 6.0 Hz, 6H), AnalCalcd for (C20H21N2O6PS + 0.25 HBr): C, 51.26 H, 4.57; N. 5.98. Found:C, 51.19; H, 4.54; N, 5.69. 128

477.4 (+) 7.70 (m, 2 H), 7.53 (m, 2 7.32 (s, 1H), 7.26 (s, 1H), 6.75 (m,1H), 5.22 (s, 2H), 4.71 (m, 1 H), 2.62 (s, 3H 2.20 (s, 3H), 1.27 (d, J =5.7 Hz, 6H). Anal Calcd for (C22H25N2O6PS + 0.15 HBr): C, 54.08 H, 5.19;N, 5.73 Found: C, 54.32; H, 5.03; N, 5.33. 129

463.0 (+) 7.71 (m, 2 H), 7.54 (m, 2H), 7.33 (d, J = 1.8 Hz, 1H), 7.27(d, J = 1.8 Hz, 1H), 7.23 (d, J = 1.2 Hz, 1H), 6.77 (m, 1H), 5.23 (s,2H), 4.72 (m, 1 H), 2.38 (d, J = 1.2 Hz, 3H), 1.28 (d, J = 5.7 Hz, 6H),Anal Calcd for (C21H23N2O6PS + 0.1 HBr): C, 53.60 H. 4.95; N. 5.95.Found: C, 53.79; H, 5.07; N, 5.68. 130

467.4 (+) 7.34 (m, 1 H), 7.26 (m, 1H), 6.86 (m, 1H), 6.79 (m, 1H), 6.66(m, 1H), 5.17 (s, 2H), 4.72 (m, 1 H), 2.27 (d, J = 0.3 Hz, 3H), 2.20 (d,J = 0.3 Hz, 3H), 1.28 (d, J = 3.3 Hz, 6H). Anal Calcd for(C20H23N2O7PS + 1.4 H2O): C, 48.86 H, 5.29; N, 5.70, Found: C, 49.26; H,5.55; N, 5.11. 131

439.4 (+) 7.57 (d, J = 2.1 Hz, 1 H), 7.36 (m, 1H), 7.29 (m, 2H), 6.86(d, J = 1.5 Hz, 1H), 6.82 (m, 1H), 6.66 (d, J = 1.2 Hz, 1H), 5.18 (s,2H), 4.74 (m, 1 H), 1.29 (d, J = 3.6 Hz, 6H). Anal Calcd for(C18H19N2O7PS + 0.1 HBr): C, 48.42 H, 4.31; N, 6.27. Found: C, 48.52; H4.25; N, 6.09. 132

505 .4 (+) 7.77 (m, 2 H), 7.54 (m, 1H), 7.31 (m, 1H), 7.19 (m, 2H), 6.89(m, 1H), 4.80 (m, 1 H), 2.41 (s, 3H), 1.44 (s, 9H), 1.36 (d, J = 6.0 Hz,6H). Anal Calcd for (C24H29N2O6PS): C, 57.13 H, 5.79; N, 5.55. Found: C,56.92; H, 5.85; N, 5.29. 133

437.4 (+) 8.65 (d, J = 5.7 Hz, 2H),7.52 (m, 3 H), 7.26 (m, 1H), 7.05 (m,1H), 4.72 (m, 1 H), 1.28 (d, J = 6.3 Hz, 6H). Anal Calcd for(C17H17N4O6PS + 0.2 NH4Br + 0.3 NH3 + 1.0 H2O): C, 42.62 H, 4.35; N,13.16. Found: C, 42.71; H, 4.66; N, 13.36, 134

443.3 (+) ¹H NMR (500 MHz, DMSO- d₆) δ 1.29 (d, 6H, J = 6 Hz), 2.31 (s,3H), 4.75-4.77 (m, 1H), 6.87 (t, 1H, J = 2 Hz), 7.12 (dd, 2H, J = 9, 3Hz), 7.21 (s, 1H), 7.43 (s, 1H), 7.72 (dd, 2H, J = 13, 9 Hz), 7.83 (d,1H, J = 8 Hz), 7.96 (d, 1H, J = 9 Hz), 8.25 (s, 1H), 11.09 (s, 1H);Anal. Calcd. for (C₂₂H₂₃N₂O₆P + 1.7HB)r: C, 45.56; H, 4.29; N, 4.83.Found: C, 45.83; H, 4.05; N, 4.63. 135

430.1 (−) ¹H NMR (500 MHz, DMSO- d₆) δ 1.29 (d, 6H), 4.75-4.77 (m, 1H),6.86 (t, 1H), 7.13 (dd, 2H), 7.14 (s, 1H), 7.46 (s, 1H), 7.71 (dd, 2H),8.42 (d, 1H), 8.47 (s, 1H), 9.37 (s, 1H), 11.18 (s, 1H); Anal. Calcd,for (C₂₀H₂₀N₃O₆P + 1.4HBr + 0.2 Et₂O): C, 44.81; H, 4.23; N, 7.54.Found: C. 45.16; H, 4.28N, 6.75. 136

432.4 (+) ¹H NMR (500 MHz, DMSO- d₆) δ 1.29 (d, 6H), 3.77 (s, 3H),4.75-4.77 (m, 1H), 6.55 (d, 1H), 6.78 (t, 1H), 7.11 (dd, 2H), 7.17 (s,1H). 7.41 (s, 1H), 7.59 (d, 1H), 7.70 (dd, 2H), 10.88 (s, 1H); Anal.Calcd. for (C₂₀H₂₂N₃O₆P + 1.4HBr); C, 44.10; H, 4.33; N, 7.71, Found: C,44.08; H, 4.29; N, 7.46. 137

447.6 (+) ¹H NMR (500 MHz, DMSO- d₆) δ 1.29 (d, 6H), 4.74-4.77 (m, 1H),6.83 (d, 1H), 7.12 (dd, 2H), 7.20 (d, 1H), 7.43 (s, 1H), 7.41 (s, 1H),7.70 (dd, 2H), 7.77-7.81(m, 1H), 8.16 (dd, 1H), 8.39 (d, 1H), 10.98 (s,1H); Anal. Calcd, for (C₂₁H₂₀FN₂O₆P +1.4HBr): C, 45.07; H, 3.85; N.5.01, Found: C, 45.26; H, 3.76; N, 4.82. 138

446.6 (+) ¹H NMR (300 MHz, DMSO- d₆) δ 1.29 (d, 6H), 1.36 (t, 3H), 4.05(q, 2H), 4.72-4.77 (m, 1H), 6.55 (d, 1H), 6.78 (d, 1H), 7.12 (dd, 2H),7.18 (t. 1H), 7.42 (t, 1H), 7.64 (d. 1H), 7.70(dd, 2H), 10.90 (s, 1H);Anal. Calcd. for (C₂₁H₂₄N₃O₆P + 1.4HBr): C, 45.15; H, 4.58; N, 7.52.Found: C, 45,39; H, 4.58; N, 7.30. 139

465.4 (+) ¹H NMR (500 MHz, DMSO- d₆) δ 1.25 (d, 3H), 3.47-3.53 (m, 3H),4.75-4.78 (m, 1H), 6.89 (t, 1H), 7.14 (dd, 2H), 7.28 (t, 2H), 7.55 (t,2H). 7.72 (dd, 2H); Anal. Calcd. for (C₂₀H₂₁N₂O₇PS + 0.5 H₂O): C, 50.74;H, 4.68; N. 5.92. Found: C, 50.74; H, 4.59; N, 5.56. 140

499.6 (+) ¹H NMR (300 MHz,DMSO- d₆) δ 1.31 (d, 6H), 2.61 (s, 3H),4.76-4.81 (m, 1H), 6.87 (s, 1H), 7.13 (m. 2H), 7.25 (m, 2H), 7.33 (s,1H), 7.56 (s, 1H), 7.71 (bs, 2H), 7.81(d, 1H); Anal. Calcd. for(C₂₄H₂₃N₂O₆PS + 0.8 H₂O): C, 56.20; H, 4.83; N, 5.46. Found: C, 56.22;H, 4.55; N. 5.52. 141

430.1 (+) ¹H NMR (500 MHz, DMSO- d₆) δ 1.27 (d, 6H), 4.69-4.72 (m, 1H),6.75 (s, 1H). 6.99 (d, 2H), 7.11 (s, 1H), 7.25 (t, 1H), 7.30 (s, 1H).7.66 (dd, 214), 8.72 (d, 2H); Anal Calcd, for (C₂₀H₂₀N₃O₆P + 0.9 HBr +1.2 NH3): C, 45.96; H, 4.73; N, 11.26. Found: C, 45.65; H, 4.88; N,11.25. 142

377.1 (+) ¹H NMR (500 MHz, DMSO- d₆) δ 7.11-7.14 (m, 2H), 7.29 (d, 1H),7.35-7.37 (m, 1H), 7.55 (d, 2H), 7.60 (t, 1H), 7.69-7.77 (m, 2H),7.92-7.94 (m, 1H); Anal. Calcd, for (C₁₆H₁₃N₂O₅PS): C, 51.07; H, 3.48;N, 7.44. Found: C. 51.29; H, 3.70; N, 7.29. 143

436.4 (+) ¹H NMR (300 MHz, DMSO- d₆) δ 1.32 (d, 6H), 4.74-4.79 (m, 1H),6.96 (t, 1H), 7.29 (d. 1H), 7.33 (s, 1H), 7.50-7.56 (m, 3H), 7.83 (dd,1H), 8.58 (d, 1H); Anal. Calcd. for (C₁₈H₁₈N₃O₆PS): C, 49.66; H, 4.17;N, 9.65. Found: C, 49.39; H, 4.21; N, 9.38.

Examples 144-145

The following examples were prepared in a similar manner to Example 4from the appropriate intermediates with modifications evident to anindividual skilled in the art:

Mass Spect. 1H NMR δ (DMSO-d₆) & Elemental Example Structure (Mode)Analysis 144

451.4 (+) 7.93 (s, 1 H), 7.59-7.63 (m, 3 H), 7.38- 7.42 (m, 3 H),7.27-730 (m, 1 H), 4.78- 4.84 (m, 1 H), 3.06 (d, J = 21 Hz, 2 H), 1.34(d, J = 6 Hz, 6 H). Anal. Calcd, for (C₂₀H₂₀FN₂O₅PS + 0.5 H₂O): C,52.29; H, 4.61; N, 6.10. Found: C, 52.13; H, 4,44; N, 6.05. 145

467.4 (+) 7.78 (s , 1 H), 7.70 (dd J = 13,9 Hz, 2 H), 7.61 (s, 1 H),7.57 (t, J = 2 Hz, 1 H), 7.18 (s, 1H), 7.10 (dd, J = 6, 3 Hz, 2 H), 2.54(d, J = 7 Hz, 2 H), 1.91 (m, 1 H), 0.88 (d, J = 7 Hz, 6 H). Anal. Calcd.for (C₂₀H₂₀ClN₂O₅PS): C, 51.45; H, 4.32; N, 6.00. Found: C, 51.55; H,4.63; N, 5.86.

Examples 146-157

The following examples were prepared in a similar manner to Example 6from the appropriate intermediates with modifications evident to anindividual skilled in the art:

Mass Spect. 1H NMR δ (DMSO-d₆) & Example Structure (Mode) ElementalAnalysis 146

506.1 (+) 1.30 (d, 6H, J = 6 Hz), 1.61 (d, 3H, J = 15 Hz), 3.21 (s, 3H),4.65-4.74 (m, 1H), 6.98 (t, 1H, J = 2 Hz), 7.23-7.26 (m, 2H); 7.36- 7.37(m, 1H), 7.52-7.54 (m, 1H), 7.93-7.96 (m, 2H), 8.78 (t, 1H, J = 1 Hz),9.52 (t, 1H, J = 1 Hz), 11.47 (s, 1H). Anal. Calcd. for (C₂₂H₂₄N₃O₇PS +1.3HBr + 1.0 H₂O): C, 42.03; H, 4.38; N, 6.68. Found: C, 41.88; H, 4.35;N, 6.32. 147

512.5 (+) 7.96 (m, 2 H), 7,61 (m, 1H), 7.44 (m, 1H), 7.28 (m, 2H), 7.03(m, 1H), 4.80 (m, 1 H), 3.20 (s, 3H), 1.73 (d, J = 15.6 Hz, 3H), 1.32(d, J = 6.0 Hz, 6 H). Anal. Calcd. for (C20H22N3O7PS2 + 0.6 H2O): C,45.99 H, 4.48; N, 8.04. Found: C, 45.99; H, 4.27; N, 7.93. 148

521.5 (+) 11.26 (s, 1H), 9.41 (s, 1H),8.61 (s, 1H), 7.86 (m, 2H), 7.50(m, 1H), 7.35 (m, 1H), 7.22 (m, 2H), 6.94 (m, 1H), 4.75 (m, 1 H), 3.26(m, 2H), 1.28 (d, J = 6.0 Hz, 6 H), 1.09 (m, 3H). Anal. Calcd. for(C22H24N3O8PS + 0.1 NH4I + 0.2 NH4OH): C, 48.66 H, 4.71; N, 8.51. Found:C, 48.56; H, 4.82; N, 8.80. 149

520.5 (+) 11.26 (s, 1H), 9.40 (s, 1H), 8.61 (s, 1H), 7.87 (m, 2 H), 7.50(m, 1H), 7.35 (m, 1H), 7.22 (m, 2H), 6.94 (m, 1H), 4.75 (m, 1 H), 3.25(m, 2H), 1.28 (d, J = 6.0 Hz, 6 H), 1.09 (m, 3H). Anal. Calcd. for(C23H26N3O7PS + 0.8 H2O): C, 51.74 H, 5.21; N, 7.87. Found: C, 51.79; H,5.05; N, 8.13. 150

536.5 (+) 11.31 (s, 1H), 9.45 (s, 1H), 8.64 (s, 1H), 7.84 (m, 2 H), 7.52(m, 1H), 7.37 (m, 1H), 7.23 (m, 2H), 6.96 (m, 1H), 4.76 (m, 1 H), 3.37(m, 1H), 1.29 (d, J = 6.0 Hz, 6H), 1.15 (d, J = 6.6 Hz, 6H). Anal.Calcd. for (C23H26N3O8PS + 0.1 NH4I + 0.1 HI): C, 49.09 H, 4.75; N,7.72. Found: C, 48.82; H, 4.37; N, 8.10. 151

534.5 (+) 11.42 (s, 1H), 9.49 (s, 1H), 8.75 (s, 1H), 7.84 (m, 2 H), 7.52(m, 1H), 7.37 (m, 1H), 7.24 (m, 2H), 6.98 (m, 1H), 4.77 (m, 1 H), 3.37(m, 1H), 1.55 (d, J = 15.0 Hz, 3H), 1.29 (d, J = 6.3 Hz, 6 H), 1.14 (d,J = 6.9 Hz, 6H). Anal. Calcd. for (C24H28N3O7PS + 0.5 H2O): C, 53.13 H,5.39; N, 7.74. Found: C, 52.94; H, 5.08; N, 7.85. 152

535.5 (+) 11.05 (s, 1H), 8.55 (d, J = 5.5 Hz, 1H), 8.17 (d, J = 8.0 Hz,1H), 7.98 (m, 1H), 7.83 (d, J = 8.5 Hz, 2 H), 7.49 (s, 1H), 7.35 (s,1H), 7.22 (d, J = 8.5 Hz, 2H), 6.93 (m, 1H), 4.77 (m, 1 H), 3.37 (m,1H), 1.28 (d, J = 6.0 Hz, 6H), 1.14 (d, J = 6.5 Hz, 6H). Anal. Calcd.for (C24H27N2O8PS + 0.2 NH4I): C, 51.15 H, 4.97; N, 5.47. Found: C,51.44; H, 5.09; N, 5.48. 153

533.5 (+) 11.14 (s, 1H), 8.63 (s, 1H), 8.24 (d, J = 8.0 Hz, 1H), 8.09(m, 1H), 7.84 (d, J = 9 Hz, 2 H), 7.49 (s, 1H), 7.35 (s, 1H), 7.23 (d, J= 9 Hz, 2H), 6.95 (m, 1H), 4.77 (m, 1 H), 3.37 (m, 1H), 1.52 (d, J =14.5 Hz, 3H), 1.28 (d, J = 6 Hz, 6H), 1.14 (d, J = 7.0 Hz, 6H). Anal.Calcd. for (C25H29N2O7PS + 0.2 HI + 0.2 H2O): C, 53.11 H, 5.35; N, 4.96.Found: C, 53.13 H, 4.96; N, 4.93. 154

521.5 (+) 11.10 (s, 1H), 8.56 (s, 1H), 8.22 (d, J = 8.5 Hz, 1H), 8.02(m, 1H), 7.87 (m, 2 H), 7.49 (s, 1H), 7.34 (s, 1H), 7.23 (m, 2H), 6.94(m, 1H), 4.77 (m, 1 H), 3.26 (m, 2H), 1.28 (d, J = 6.0 Hz, 6 H), 1.09(m, 3H). Anal. Calcd. for (C23H25N2O8PS + 0.1 HI): C, 51.80 H, 4.74; N,5.25. Found: C, 51.80; H, 4.76; N, 5.11. 155

511.0 (+) 7.95 (d, J = 9 Hz, 2 H), 7.85 (d, J = 5 Hz, 1 H), 7.57 (m, 1H), 7.40 (m, 1H), 7.25 (d, J = 9 Hz, 2 H), 7.00 (m, 1 H), 4.77-4.80 (m,1 H), 3.22 (s, 3 H), 1.59 (d, J = 15 Hz, 3 H), 1.31 (d, J = 6 Hz, 6 H).Anal. Calcd. for (C22H23N2O8PS + 0.5 HBr): C, 47.38; H, 4.67; N, 5.53.Found: C, 47.65; H, 4.47; N, 5.28. 156

508.4 (+) 1.31 (d, 6H, J = 6 Hz), 3.21 (s, 3H), 4.76-4.81 (m, 1H), 6.98(t, 1H, J = 2 Hz), 7.25 (dd, 2H, J = 7, 2 Hz), 7.36-7.37 (m, 1H),7.53-7.54 (m, 1H), 7.95 (dd, 2H, J = 7, 2 Hz), 8,70 (t, 1H, J = 1 Hz),9.52 (t, 1H, J = 1 Hz), 11.42 (s, 1H). Anal. Calcd. for C₂₁H₂₂N₃O₈PS: C,49.70; H, 4.37; N, 8.28. Found: C, 49.72; H, 4.26; N, 8.30. 157

514.5 (+) 7.94 (m, 2 H), 7.58 (m, 1H), 7.40 (m, 1H), 7.26 (m, 2H), 6.99(m, 1H), 4.76 (m, 1 H), 3.20 (s, 3H), 1.31 (d, J = 6.0 Hz, 6H). Anal.Calcd. for (C19H20N3O8PS2 + 0.2 NH4Br + 0.5 H2O): C, 42.10 H, 4.05; N,8.27. Found: C, 42.47; H, 4.40; N, 8.64.

Examples 158-163

The following examples were prepared in a similar manner to Example 10from the appropriate intermediates with modifications evident to anindividual skilled in the art:

Mass Spect. 1H NMR δ (DMSO-d₆) & Elemental Example Structure (Mode)Analysis 158

461.6 (+) 0.96 (d, 3H, J = 7 Hz), 1.01 (d, 3H, J = 7 Hz), 1.31 (d, 6H, J= 6 Hz), 1.91 (septet, 1H, J = 7 Hz), 4.77 (septet, 1H, J = 6 Hz), 6.89(t, 1H, J = 2 Hz), 7.16 (dd, 2H, J = 9, 2 Hz), 7.32 (t, 1H, J = 2 Hz),7.29 (d, 1H, J = 4 Hz), 7.32 (t, 1H, J = 2 Hz), 7.53 (t, 1H, J = 2 Hz),7.56 (d, 1H, J = 4 Hz), 7.72 (dd, 2H, J = 10, 9 Hz). Anal, calcd. for(C₂₂H₂₅N₂O₅PS): C, 57.38; H, 5.47; N, 6.08. Found: C, 57.24; H, 5.40; N,6.01. 159

484.1 (+) 8.18 (dd, J = 5, 2 Hz, 1 H), 7.92 (d, J = 11 Hz, 1 H), 7.61(s, 1 H), 7.53 (s, 1 H), 7.40 (s, 1 H), 6.99 (m, 1 H), 4.75 (m, 1 H),2.36 (s, 3H), 1.31 (d, J = 6 Hz, 6H). Anal. Calcd. for (C₁₉H₁₉ClN₃O₆PS +1.2 H₂O): C, 45.15; H, 4.27; N, 8.31. Found: C, 44.97; H, 4.14; N, 8.16.160

494.4 (+) 8.04 (m, 1 H), 7.91 (m, 1 H), 7.61 (s, 1 H), 7.57 (s, 1 H),7.42 (s, 1 H), 7.12 (m, 2H), 4.78 (m, 1 H), 1.31 (d, J = 6 Hz, 6 H).Anal. Calcd. for (C₂₀H₁₇ClN₃O₆PS + 1.1 HBr): C, 41.21; H, 3.13; N, 7.21.Found: C, 41.29; H, 3.05; N, 6.89. 161

499.6 (+) 7.67 (m, 1 H), 7.61 (d, J = 2 Hz, 1 H), 7.50 (s, 1 H), 7.29(s, 1 H), 6.87 (d, J = 2 Hz, 1 H), 6.80 (d, J = 5 Hz; 1H), 6.59 (d, J =8 Hz, 1 H), 4.75 (m, 1H), 3.78 (s, 3H), 1.29 (m, 6 H). Anal. Calcd, for(C₂₀H₂₀ClN₂O₇PS + 0.9 H₂O): C, 46.64; H, 4.27; N, 5.44. Found: C, 46.76;H, 4.27; N, 5.27. 162

471.4 (+) 8.72 (d, J = 1 Hz, 1 H), 8.46 (s, 1 H), 7.62 (d, J = 1 Hz, 1H), 7.57 (d, J = 1 Hz, 1 H), 7.50 (s, 1 H), 7.14 (t, J = 2 Hz, 1H), 4.75(m, 1H), 1.30 (d, J = 6 Hz, 6 H). Anal Calcd. for (C₁₇H₁₆ClN₄O₆PS): C,43.37; H, 3.43; N, 11.90. Found: C, 43.62; H, 3.47; N, 11.61. 163

471.1 (+) 8.01 (dd, J = 9, 5 Hz, 1 H), 7.62 (s, 1 H), 7.4-7.6 (m, 3 H),7.16 (t, J = 2 Hz, 1 H), 4.7-4.8 (m, 1 H), 1.32 (d, J = 6 Hz, 6 H).Anal. Calcd. for (C₁₇H₁₆ClN₄O₆PS + 0.3 H₂O): C, 42.88; H, 3.51; N,11.76. Found: C, 42.85; H, 3.21; N, 11.56.

Examples 164-165

The following examples were prepared in a similar manner to Example 11from the appropriate intermediates with modifications evident to anindividual skilled in the art:

Mass Spect. 1H NMR δ (DMSO-d₆) & Example Structure (Mode) ElementalAnalysis 164

473.4 (+) δ 7.57 (m, 3 H), 7.25 (m, 1H), 7.07 (m, 1H), 6.97 (m, 1H),4.70 (m, 1 H), 4.19 (s, 2H), 1.27 (m, 6H). Anal Calcd for(C18H18ClN2O5PS2 + 0.1 HBr): C, 44.95 H, 3.79; N, 5.82. Found: C, 45.05;H, 3.75; N, 5.88. 165

457.1 (+) 7.51 (d, J = 7.2 Hz, 2 H), 7.37 (d, J = 2.4 Hz, 1H), 7.23 (m,1H), 7.06 (s, 1H), 6.96 (s, 1H), 4.70 (m, 1 H), 4.18 (s, 2H), 1.27 (d, J= 6.0 Hz, 6H). Anal Calcd for (C18H18FN2O5PS2 + 0.1 HBr): C, 46.54 H,3.93; N, 6.03. Found: C, 46.40; H, 4.14; N, 5.93.

Examples 166-167

The following examples were prepared in a similar manner to Example 14from the appropriate intermediates with modifications evident to anindividual skilled in the art:

Mass Spect. 1H NMR δ (DMSO-d₆) & Example Structure (Mode) ElementalAnalysis 166

579.6 (+) 12.93 (s, 1 H), 7.95 (m, 2H), 7.58 (d, J = 1.8 Hz, 1 H), 7.51(s, 1H), 7.40(m, 1H), 7.25 (m, 2H), 6.94 (m, 2H), 6.77 (m, 1H), 4.78 (m,1 H), 3.21 (s, 3H), 1.30 (d, J = 5.7 Hz, 6 H). Anal Calcd for(C24H23N2O9PS2 + 0.1 HBr): C, 49.14 H, 3.97; N, 4.78. Found: C, 48.96;H, 3.94; N, 4.59. 167

589.4 (+) 8.00 (m, 2H), 7.94 (m, 2 H), 7.80 (s, 1H), 7.73 (m, 2H), 7.60(m, 1H), 7.41 (m, 1H), 7.25 (m, 2H), 6.97 (m, 1H), 4.79 (m, 1 H), 3.20(s, 3H), 1.30 (d, J = 6.0 Hz, 6 H). Anal Calcd for (C26H25N2O8PS2 + 0.6HBr): C, 49.01 H, 4.05; N, 4.40. Found: C, 49.09; H, 3.72; N, 4.13.

Examples 168-171

The following examples were prepared in a similar manner to Example 16from the appropriate intermediates with modifications evident to anindividual skilled in the art:

Mass Spect. 1H NMR δ (DMSO-d₆) & Example Structure (Mode) ElementalAnalysis 168

525.6 (+) 7.95 (dd, J = 7.2 Hz, 2 H), 7.54 (s, 1 H), 7.37 (t, J = 2 Hz,1 H), 7.26 (m, 4H), 6.96 (t, J = 2 Hz, 1 H), 4.77 (m, 1 H), 3.20 (m, 5H), 1.30 (m, 9 H). Anal. Calcd. for (C₂₂H₂₅N₂O₇PS₂): C, 50.38; H, 4.80;N, 5.34. Found: C, 50.24; H, 4.94; N, 5.11. 169

527.6 (+) 7.94 (dd, J = 7, 2 Hz, 2 H), 7.54 (d, J = 2 Hz, 1H), 7.37 (t,J = 2 Hz, 1 H), 7.26 (m, 3H), 6.96 (t, J = 2 Hz, 1H), 4.77 (m, 1 H),3.21 (s, 3 H), 3.10 (d, J = 20 Hz, 2 H), 1.30 (d, J = 6 Hz, 2 H). Anal.Calcd. for (C₂₁H₂₃N₂O₈PS₂ + 0.2 H₂O): C, 47.58; H, 4.45; N, 5.28. Found:C, 47.61; H, 4.40; N, 5.01. 170

557.6 (+) δ 7.95 (dd, J = 7, 2 Hz, 2 H), 7.55 (d, J = 2 Hz, 1 H), 7.51(s, 1H), 7.38 (t, J = 2 Hz, 1 H), 7.25 (dd, J = 7, 2 Hz, 2 H), 6.97 (t,J = 2 Hz, 1 H), 4.77 (m, 1 H), 4.73 (s, 2 H), 3.54 (d, J = 9 Hz, 2 H),3.21 (s, 3 H), 1.30 (d, J = 6 Hz, 2 H). Anal. Calcd. for(C₂₂H₂₅N₂O₉PS₂ + 0.2 H₂O + 0.3 TMS-OH): C, 46.84; H, 4.87; N, 4.77.Found: C, 46.89; H, 4.51; N, 4.36. 171

507.4 (+) 10.78 (s, 1 H), 8.32 (d, J = 1.5 Hz, 1H), 8.13 (d, J = 6.8 Hz,1 H), 7.79 (m, 1 H), 7.46 (m, 1H), 7.31(m, 1H), 7.18 (m, 2H), 7.11 (m,1H), 6.63 (m, 1H), 4.70 (m, 1 H), 4.52 (s, 2H), 4.24 (m, 2H), 3.35 (d, J= 8.4 Hz, 2H), 3.04 (m, 2H), 1.25 (d, J = 6.0 Hz, 6 H). Anal Calcd for(C23H27N2O7PS + 0.1 NH4Br + 0.7 NH3): C, 52.30 H, 5.63; N, 7.42. Found:C, 52.36: H, 5.58; N, 7.37.

Examples 172-173

The following examples were prepared in a similar manner to Example 23from the appropriate intermediates with modifications evident to anindividual skilled in the art:

Mass Spect. 1H NMR δ (DMSO-d₆) & Elemental Example Structure (Mode)Analysis 172

467.4 (+) 7.57 (s, 1 H), 7.53 (dd, J = 8, 5 Hz, 2 H), 7.52 (m, 1 H),7.46 (m, 1H), 7.24 (dd, J = 8, 3 Hz, 2 H), 6.99 (m, 1 H), 6.65-4.71 (m,1 H), 3.94 (s, 2 H), 1.25 (d, J = 6 Hz, 6 H). Anal, calcd. for(C₂₀H₂₀ClN₂O₅PS + 0.3 NH₄Cl): C, 49.74; H, 4.76; N, 6.67. Found: C,49.68; H, 4.74; N, 6.83. 173

451.4 (+) 7.59 (dd, J = 12, 8 Hz, 2 H), 7.49 (m, 1 H), 7.46 (m, 1 H),7.37 (d, J = 3 Hz, 1 H), 7.35 (dd, J = 8, 3 Hz, 2 H), 7.02 (m, 1 H),4.66-4.71 (m, 1 H), 3.98 (s, 2 H), 1.26 (d, J = 6 Hz). Anal. calcd. for(C₂₀H₂₀FN₂O₅PS + 0.4 H₂O): C, 52.49: H, 4.58; N, 6.12. Found: C, 52.45;H, 4.56; N, 5.91.

Examples 174-176

The following examples were prepared in a similar manner to Example 26from the appropriate intermediates with modifications evident to anindividual skilled in the art:

Mass Spect. 1H NMR δ (DMSO-d₆) & Example Structure (Mode) ElementalAnalysis 174

477.4 (+) 7.70 (dd, J = 12, 8 Hz, 2 H), 7.55 (d, J = 4 Hz, 1 H), 7.50(d, J = 1 Hz, 1H), 730 (m, 2 H), 7.10 (d, J = 8 Hz, 1 H), 6.85 (s, 1 H),4.75 (m, 1 H), 1.29 (d, J = 6 Hz, 6 H), 1.14 (d, J = 6 Hz, 6 H). AnalCalcd. for (C₂₂H₂₅N₂O₆PS + 0.8 H₂O); C, 53.83; H, 5.46; N, 5.71. Found:C, 53.67; H, 5.02; N, 5.23. 175

503.6 (+) 7.71 (m, 2 H), 7.56 (s, 1 H), 7.52 (t, J = 2 Hz, 1H), 7.32(dd, J = 2, 1 Hz, 2 H), 7.15 (m, 2 H), 6.89 (t, J = 2 Hz, 1 H), 4.76 (m,1 H), 4.69 (m, 1 H), 1.65 (m, 6 H), 1.51 (m, 2 H), 1.30 (d, J = 6 Hz,6H). Anal. Calcd. for (C₂₄H₂₇N₂O₆PS): C, 57.36; H, 5.42: N, 5.57. Found:C, 57.22; H, 5.38; N, 5.54. 176

493.6 (+) 7,72(dd, J = 13, 9 Hz, 2 H), 7.56 (s, 1 H), 7.53 (d, J = 1 Hz,1H), 7.32 (d, J = 2, Hz, 1 H), 7.28 (d, J = 3 Hz, 1 H), 7.15 (m, 2 H),6.89 (t, J = 2 Hz, 1 H), 4.76 (m, 1 H), 3.92 (m, 2 H), 3.46 (t, J = 5Hz, 2 H), 3.21 (s, 3H), 1.30 (d, J = 6 Hz, 6H); LCMS m/z = 493.6[C₂₂H₂₅N₂O₇PS + H]⁺; Anal. Calcd. for (C₂₂H₂₅N₂O₇PS): C, 53.65; H, 5.12;N, 5.69. Found: C, 53.56; H, 5.06; N, 5.59.

Example 177 2,2-Dimnethyl-propionic acid1-(hydroxy-{4-[3-isopropoxy-5-(thiazol-2-ylcarbamoyl)-phenoxy]-phenyl}-phosphinoyloxy)-ethylester

A mixture of{4-[3-isopropoxy-5-(thiazol-2-ylcarbamoyl-)phenoxy]-phenyl}-phosphonicacid (250 mg, 0.58 mmol) and DIEA (0.193 mL, 1.16 mmol) in 6 mL ofacetonitrile was stirred for 15 min and then 1-iodoethyl pivalate (177mg, 0.69 mmol) was added. The resulting mixture was stirred for 2 h atrt, then diluted with CH₂Cl₂, washed with 1 M aqueous NaHSO₄, dried(MgSO₄) and evaporated. The residue was dissolved in 3:1acetonitrile/water and subjected to MPLC purification through a 25 g C18column eluting with % acetonitrile in water (time): 15-50 (15 min).Lyophilization of the eluent containing the desired product provided 31mg (10%) of the title compound as an amorphous solid: ¹H NMR (500 MHz,DMSO-d₆): δ 0.91 (s, 9H), 1.29 (d, 6H, J=6 Hz), 1.30 (d, 3H, J=6 Hz),4.73 (septet, 1H, J=6 Hz), 6.34 (br s, 1H), 6.75 (s, 1H), 7.01 (d, 2H,J=7 Hz), 7.24 (s, 1H), 7.28 (d, 1H, J=3 Hz), 7.45 (s, 1H), 7.56 (d, 1H,J=3 Hz), 7.63 (br s, 2H), 12.61 (br s, 1H); LCMS (m/z): 563.4[C₂₆H₃₁N₂O₈PS+H]⁺. Anal. calcd. for (C₂₆H₃₁N₂O₈PS+1H₂O): C, 53.79; H,5.73; N, 4.82. Found: C, 52.93; H, 5.93; N, 5.92.

Example 178(4-{3-Isopropoxy-5-[(5-methyl-2-oxo-[1,3]dioxol-4-ylmethyl)-thiazol-2-yl-carbamoyl]-phenoxy}-phenyl)-phosphonicacid mono-(5-methyl-2-oxo-[1,3]dioxol-4-ylmethyl) ester

The title compound was prepared from{4-[3-isopropoxy-5-(thiazol-2-ylcarbamoyl-)phenoxy]-phenyl}-phosphonicacid and 5-methyl-2-oxo-1,3-dioxolen-4-yl)methylbromide according to themethod described in Example 177 with modifications evident to anindividual skilled in the art. ¹H NMR (500 MHz, DMSO-d₆): δ 1.29 (d, 6H,J=6 Hz), 2.07 (s 3H), 2.14 (s, 3H), 4.71 (septet, 1H, J=6 Hz), 4.76 (d,2H, J=10 Hz), 5.40 (s, 2H), 6.84 (t, 1H J=2 Hz), 7.11 (dd, 2H, J=8, 3Hz), 7.12 (d, 1H, J=5 Hz), 7.43 (dd, 1H, J=2, 1 Hz), 7.59 (dd, 2H, J=2,1 Hz), 7.61 (d, 1H, J=5 Hz), 7.70 (dd, 2H, J=12, 8 Hz); LCMS (m/z):658.8 [C₂₉H₂₇N₂O₁₂PS+H]⁺. Anal. calcd. for (C₂₉H₂₇N₂O₁₂PS): C, 52.89; H,4.13; N, 4.25. Found: C, 52.83; H, 4.43; N, 4.10.

Example 179 3-Methyl-thiobutyric acid2-{{4-[3-isopropoxy-5-(thiazol-2-ylcarbamoyl)phenoxy]phenyl}[2(3methylbutyrylsulfanyl)ethoxy]phosphinoyloxy}ethylester

To a solution of{4-[3-isopropoxy-5-(thiazol-2-ylcarbamoyl)-phenoxy]-phenyl}-phosphonicacid (Example 3) (800 mg, 1.84 mmol) in THF (20 mL) was addedtriphenylphosphine (1.21 g, 4.60 mmol), 3-methyl-thiobutyric acidS-(2-hydroxy-ethyl) ester (746 mg, 4.60 mmol) anddiisopropylazodicarboxylate (906 μL. 4.60 mmol). The resulting mixturewas stirred at rt for 3 hr. The crude reaction mixture was concentratedunder vacuum. The residue was chromatographed on silica gel using anethyl acetate-hexanes gradient to afford 82 mg (6%) of the titlecompound: ¹H NMR (300 MHz, DMSO-d₆): δ 12.70 (bs, 1H), 7.73 (dd, J=13, 9Hz, 2H), 7.55 (t, 2H), 7.36 (d, J=2 Hz, 1H), 7.28 (s, 1H), 7.18 (t, J=4Hz, 2H), 6.91 (d, J=2 Hz, 1H), 4.76 (m, 1H), 4.06 (m, 4H), 3.15 (m, 4H),4.95 (m, 4H), 2.01 (m, 2H), 1.30 (d, J=6 Hz, 6H), 0.87 (d, J=7 Hz, 12H);LCMS m/z=723.4 [C₃₃H₄₃N₂O₈PS₃+H]⁺; Anal. Calcd. for (C₃₃H₄₃N₂O₈PS₃): C,54.83; H, 6.00; N, 3.88. Found: C, 55.49; H, 5.36; N, 3.92.

Example 180 2,2-Dimethyl-propionic acid(2,2-dimethyl-propionyloxymethoxy){4-[3-isopropoxy-5-(thiazol-2-ylcarbamoyl)phenoxy]phenyl}phosphinoyloxymethylester

To a solution of{4-[3-isopropoxy-5-(thiazol-2-ylcarbamoyl)-phenoxy]-phenyl}-phosphonicacid (Example 3) (200 mg, 0.459 mmol) in acetonitrile (10 mL) was addeddiisopropylethylamine (155 μL, 0.941 mmol). Let stir until mixture goesinto solution. Add 2,2-dimethyl-propionic acid iodomethylester and stirat rt for 16 h. The residue was adsorbed onto SiO₂ and chromatographedon silica gel using an ethyl acetate-hexanes gradient to afford 50 mg(16%) of the title compound as an oil: ¹H NMR (300 MHz, DMSO-d₆): δ12.68 (bs, 1H), 7.74 (dd J=13, 9 Hz, 2H), 7.55 (d, J=4 Hz, 2H), 7.29 (m,4H), 6.85 (s, 1H), 5.66 (m, 4H), 4.76 (m, 1H), 1.31 (d, J=6 Hz, 6H),1.07 (s, 18H); LCMS m/z=663.9 [C₃₁H₃₉N₂O₁PS+H]⁺; Anal. Calcd. for(C₃₁H₃₉N₂O₁₀PS): C, 56.19; H, 5.93; N, 4.23. Found: C, 56.41; H, 6.08;N, 4.00.

Example 181 2,2-Dimethylpropionic acid1-([1-(2,2-dimethyl-propionyloxy)ethoxy]{4-[3-isopropoxy-5-(thiazol-2-ylcarbamoyl)phenoxy]phenyl}phosphinoyloxy)ethylester

Prepared from{4-[3-isopropoxy-5-(thiazol-2-ylcarbamoyl)-phenoxy]-phenyl}-phosphonicacid (Example 3) in a similar manner to Example 177 from the appropriateintermediates with modifications evident to an individual skilled in theart: ¹H NMR (300 MHz, DMSO-d₆): δ 12.68 (bs, 1H), 7.72 (m, 2H), 7.54 (m,2H), 6.86 (d, J=24 Hz, 1H), 6.48 (m, 2H), 4.75 (m, 1H), 1.49 (dd, J=14,S Hz, 6H), 1.31 (d, J=6 Hz, 6H), 1.01 (m, 18H); LCMS m/z=691.9[C₃₃H₄₃N₂O₁₀PS+H]⁺; Anal. Calcd. for (C₃₃H₄₃N₂O₁₀PS): C, 57.38; H, 6.27;N, 4.06. Found: C, 57.16; H, 6.32; N, 3.89.

Example 182{4-[3-Isopropoxy-5-(thiazol-2-ylcarbamoyl)phenoxy]phenyl}phosphonic acidbis-(1-isopropoxycarbonyloxymethyl) ester

Prepared from{4-[3-isopropoxy-5-(thiazol-2-ylcarbamoyl)-phenoxy]-phenyl}-phosphonicacid (Example 3) in a similar manner to Example 177 from the appropriateintermediates with modifications evident to an individual skilled in theart: ¹H NMR (300 MHz, DMSO-d₆): δ 12.70 (bs, 1H), 7.71 (m, 2H), 7.55 (d,J=3 Hz, 2H), 7.33 (m, 2H), 7.17 (m, 2H), 6.87 (m, 1H), 6.40 (m, 2H),4.77 (m, 2H), 4.60 (m, 1H), 1.52 (m, 6H), 1.15 (m, 18H); LCMS ml: =695.4[C₃₁H₃₉N₂O₁₂PS+H]⁺; Anal. Calcd. for (C₃₁H₃₉N₂O₁₂PS): C, 53.60; H, 5.66;N, 4.03. Found: C, 53.67; H, 5.75; N, 3.77.

Example 183(4-{3-[(3-Fluoro-4-methoxybenzyl)thiazol-2-yl-carbamoyl]-5-isopropoxyphenoxy}phenyl)-phosphonicacid bis-(3-fluoro-4-methoxy-benzyl) ester

Prepared from{4-[3-isopropoxy-5-(thiazol-2-ylcarbamoyl)-phenoxy]-phenyl}-phosphonicacid (Example 3) in a similar manner to Example 177 from the appropriateintermediates with modifications evident to an individual skilled in theart: ¹H NMR (300 MHz, DMSO-d₆): δ 7.75 (m, 3H), 7.57 (dd, J=2, 1 Hz,1H), 7.42 (dd, J=2, 1 Hz, 1H), 7.28 (dd, J=12, 2 Hz, 1H), 7.13 (m, 11H),6.87 (t, J=3 Hz, 1H), 5.36 (s, 2H), 4.93 (m, 4H), 4.70 (m, 1H), 3.80 (s,6H), 3.77 (s, 3H), 1.29 (d, J=6 Hz, 6H); LCMS m/z=849.9[C₄₃H₄₀F₃N₂O₉PS+H]⁺; Anal. Calcd. for (C₄₃H₄₀F₃N₂O₉PS): C, 60.85; H,4.75; N, 3.30. Found: C, 60.70; H, 4.59; N, 3.16.

Example 184{4-[3-Isopropoxy-5-(thiazol-2-ylcarbamoyl)phenoxy]phenyl}phosphonic acidbis-(3-fluoro-4-methoxybenzyl) ester

To a solution of3-{4-[bis-(3-fluoro-4-methoxy-benzyloxy)-phosphoryl]-phenoxy}-5-isopropoxy-benzoicacid (350 mg, 0.557 mmol) in DMF (6 mL) was added 2-aminothiazole (70mg, 0.696 mmol), HATU (265 mg, 0.696 mmol), and diisopropylethylamine(368 μL. 2.23 mmol). Stirred at rt for 16 h. The reaction mixture wasdiluted with EtOAc and washed with H2O (2×) and brine (2×). Dried withMgSO₄, filtered, and concentrated. The residue was chromatographed onsilica gel using an ethyl acetate-hexanes gradient to provide 164 mg(42%) of the title compound: ¹H NMR (300 MHz, DMSO-d₆): δ 12.68 (bs,1H), 7.75 (dd, J=13, 9 Hz, 2H), 7.55 (d, J=4 Hz, 2H), 7.35 (s, 1H), 7.16(m, 9H), 6.91 (s, 1H), 4.97 (dd, J=8, 2 Hz, 4H), 4.76 (m, 1H), 3.82 (s,6H), 1.30 (d, J=6 Hz, 6H); LCMS m/z=711.6 [C₃₃H₃₃F₂N₂O₈PS+H]⁺; Anal.Calcd. for (C₃₅H₃₃F₂N₂O₈PS+1.2H₂O): C, 57.41; H, 4.87; N, 3.83. Found:C, 57.06; H, 4.24; N, 3.91.

Intermediates for the preparation of Example 184 were prepared accordingto Route 11, as described below.

Route 11

Step A 3-[4-(Diisopropoxy-phosphoryl)-phenoxy]-5-isopropoxy-benzoic acid2-trimethylsilanyl-ethyl ester

To a solution of3-[4-(diisopropoxy-phosphoryl)-phenoxy]-5-isopropoxy-benzoic acid(Example 3, route 3, step E) (10 g, 22.9 mmol) in DCM (115 mL) was addedDMF (0.09 mL, 1.15 mmol) and oxalyl chloride (4.0 mL, 45.8 mmol). Theresulting mixture was stirred at rt for 2 h. The mixture wasconcentrated. The resulting residue was azeotroped with 50 mL anhydroustoluene and then re-dissolved in DCM (40 mL), cooled to 0° C. A solutionof pyridine (3.1 mL, 36.6 mmol) in DCM (10 mL) was added slowly to thereaction flask followed by 2-trimethylsilanylethanol (3.6 mL, 25.2mmol). The resulting mixture was stirred at rt overnight. On second daysolvents were removed and the residue was partitioned between EtOAc andsaturated sodium bicarbonate. The organic layer was separated, washedwith brine (1×), dried with anhydrous MgSO₄, filtered, and concentrated.The residue was chromatographed on silica gel using an ethylacetate-hexanes gradient to afford 5.0 g (41%) of3-[4-(diisopropoxy-phosphoryl)-phenoxy]-5-isopropoxy-benzoic acid2-trimethylsilanyl-ethyl ester. ¹H NMR (500 MHz, DMSO-d₆): δ 7.72 (dd,J=13, 9 Hz, 2H), 7.26 (dd, J=3, 2 Hz, 1H), 7.16 (dd, J=9, 3 Hz, 2H),7.06 (dd, J=3, 2 Hz, 1H), 6.99 (t, J=3 Hz, 1H), 4.69 (m, 1H), 4.54 (m,2H), 3.48 (t, 2H), 1.28 (dd, J=8, 3 Hz, 12H), 1.18 (d, J=6 Hz, 6H), 1.04(t, 2H),−0.16 (s, 9H).

Step B 3-Isopropoxy-5-(4-phosphono-phenoxy)-benzoic acid2-trimethylsilanyl-ethyl ester

To a solution of3-[4-(diisopropoxy-phosphoryl)-phenoxy]-5-isopropoxy-benzoic acid2-trimethylsilanyl-ethyl ester (5.0 g, 9.30 mmol) in CH₂Cl₂ (100 mL) wasadded HMDS (31.7 Ml, 149 mmol), and TMS-Br (9.8 mL, 74.5 mmol). Themixture was stirred at rt for 16 h. The solvent was evaporated and theresidue was diluted with water and acidified to pH 2-3 with aqueous HCl.Extracted into EtOAc (2×). The extract was washed with dilute HC, water,and brine. Dried (MgSO₄) and evaporated to provide 2.74 g of3-Isopropoxy-5-(4-phosphono-phenoxy)-benzoic acid2-trimethylsilanyl-ethyl ester. ¹H NMR (500 MHz, DMSO-d₆): δ 7.71 (dd,J=13, 9 Hz, 2H), 7.22 (dd, J=3, 2 Hz, 1H), 7.11 (dd, J=9, 3 Hz, 2H),7.03 (dd, J=3, 2 Hz, 1H), 6.92 (t, J=3 Hz, 1H), 4.67 (m, 1H), 4.34 (t,2H), 1.27 (d, J=6 Hz, 6H), 1.05 (t, 2H), 0.01 (s, 9H).

Step C3-{4-[Bis-(3-fluoro-4-methoxy-benzyloxy)-phosphoryl]-phenoxy}-5-isopropoxy-benzoicacid 2-trimethylsilanyl-ethyl ester

To a solution of 3-isopropoxy-5-(4-phosphono-phenoxy)-benzoic acid2-trimethylsilanyl-ethyl ester (532 mg, 1.17 mmol) in ACN (15 mL) wasadded diisopropylethylamine (425 μL, 2.57 mmol), and benzyl bromide (640mg, 2.92 mmol). Stirred at 55° C. for 16 h. The reaction mixture wascooled to rt and adsorbed onto SiO₂ and chromatographed on silica gelusing an ethyl acetate-hexanes gradient to provide 536 mg (63%) of3-{4-[bis-(3-fluoro-4-methoxy-benzyloxy)-phosphoryl]-phenoxy}-5-isopropoxy-benzoicacid 2-trimethylsilanyl-ethyl ester. ¹H NMR (300 MHz, DMSO-d₆): δ 7.74(dd, J=13, 9 Hz, 2H), 7.26 (dd, J=2, 1 Hz, 1H), 7.20 (s, 1H), 7.15 (m,7H), 7.07 (m, 1H), 6.98 (m, 1H), 4.97 (dd, J=8, 2 Hz, 4H), 4.67 (m, 1H),4.34 (t, J=8 Hz, 2H), 3.82 (s, 6H), 1.27 (d, J=6 Hz, 6H), 1.03 (t, J=9Hz, 2H), 0.01 (s, 9H).

Step D3-{4-[Bis-(3-fluoro-4-methoxy-benzyloxy)-phosphoryl]-phenoxy}-5-isopropoxy-benzoicacid

To a solution of3-{4-[bis-(3-fluoro-4-methoxy-benzyloxy)-phosphoryl]-phenoxy}-5-isopropoxy-benzoicacid 2-trimethylsilanyl-ethyl ester (536 mg, 0.735 mmol) in DMF (10 mL)was added tetrabutylammonium fluoride (1.0 M solution in THF) (1.84 mL,1.84 mmol). Stirred at rt for 16 h. The reaction mixture was dilutedwith EtOAc and washed with H2O (2×) and brine (2×). Dried with MgSO₄ andevaporated solvent to provide 462 mg (100%) of3-{4-[bis-(3-fluoro-4-methoxy-benzyloxy)-phosphoryl]-phenoxy}-5-isopropoxy-benzoicacid. ¹H NMR (300 MHz, DMSO-d₆): δ 13.20 (bs, 1H), 7.74 (dd, J=13, 9 Hz,2H), 7.27 (dd, J=2, 1 Hz, 1H), 7.13 (m, 9H), 6.94 (t, J=2 Hz, 1H), 4.97(dd, J=9, 2 Hz, 4H), 4.67 (m, 1H), 3.82 (s, 6H), 1.27 (s, J=6 Hz, 6H).

Examples 185-212

The following examples were prepared according to methods used forExample 177-184 from the appropriate intermediates with modificationsevident to an individual skilled in the art:

Mass Ex- Spect. 1H NMR δ (DMSO-d₆) & ample Structure (Mode) ElementalAnalysis 185

667.6 (+) 7.82 (m, 2H), 7.49 (d, J = 4.0 Hz, 1H), 7.44 (m, 1H), 7.29 (m,1H), 7.17 (m, 3H), 6.89 (m, 1H), 5.74 (m, 4H), 4.85 (m, 2H), 4.74 (m,1H), 1.36 (d, J = 5.5 Hz, 6H) 1.25 (m, 12H). Anal Calcd for(C29H35N2O12PS): C, 52.25; H, 5.29: N, 4.20. Found: C, 52.06: H, 5.51;N, 4.17. 186

661.9 (+) 7.86 (m, 2H), 7.49 (d, J = 4.0 Hz, 1H), 7.39 (m, 1H), 7.24 (m,1H), 7.16 (d, J = 4.0 Hz, 1H), 7.13 (m, 2H), 6.84 (m, 1H), 5.00 (m, 1H),4.69 (m, 1H), 3.97 (m, 1H), 3.85 (m, 1H), 1.35 (m, 12 H), 1.26 (m, 6H),1.14 (m, 6H). Anal Calcd for (C31H41N4O8PS): C, 56.35; H, 6.25; N, 8.48.Found: C, 56.17; H, 6.04; N, 8.51. 187

785.9 (+) 7.48 (m, 3H), 7.40 (m, 1H), 7.28 (m, 10H), 7.04 (m, 2H), 6.97(m, 2H), 6.81 (m, 1H), 4.71 (m, 1H), 4.02 (m, 2H), 4.13 (m, 3H), 3.91(m, 1H), 3.16 (m, 1H), 2.92 (m, 2H), 2.72 (m, 1H), 1.36 (d, J = 6.0 Hz,6 H), 1.23 (m, 3H), 1.11 (m, 3H). Anal Calcd for (C41H45N2O8PS): C,62.74; H, 5.78; N, 7.14. Found: C, 62.55; H, 5.55; N, 6.92. 188

639.6 (+) 7.82 (m, 2H), 7.50 (d, J = 3.5 Hz, 1H), 7.45 (m, 1H), 7.30 (m,1H), 7.18 (m, 3H), 6.89 (m. 1H), 5.74 (m, 4H), 4.86 (m, 1H), 4.19 (m,4H), 1.36 (m, 6H) 1.27 (m, 12H). Anal Calcd for (C27H31N2O12PS): C,50.78: H, 4.89; N, 4.39. Found: C, 50.70; H, 5.13; N, 4.28. 189

753.4 (+) 7.87 (m, 2H), 7.49 (d, J = 3.5 Hz, 1H), 7.39 (m, 1H), 7.24 (m,1H), 7.16 (m, 3H), 6.84 (m, 1H), 4.70 (m, 1H), 4.20 (m, 2H), 4.06 (m,3H), 3.98 (m, 1H), 2.63 (m, 3H), 2.51(m, 2H), 2.05 (m, 9H), 1.90 (m,2H), 1.32 (m, 12 H), 1.16 (m, 3H). Anal Calcd for (C33H45N4O8PS3): C,52.64; H, 6.02; N, 7.44. Found: C, 53.20; H, 6.31; N, 7.38. 190

668.3 (+) 13.20 (s, 1H), 7.51 (m, 1H), 7.35 (m, 3H), 7.15 (m, 1H), 6.76(m, 1H), 5.57 (m, 1H), 4.75 (m, 1H), 4.26 (m, 1H), 3.98 (m, 6H), 3.10(m, 2H), 1.31 (m, 12H), 1.16 (m, 6H). Anal Calcd for (C28H38N5O8PS2); C,50.37; H, 5.74; N, 10.49. Found: C, 50.42; H, 6.02; N, 10.24. 191

640.4 (+) 12.67 (s, 1H), 7.85(m, 2H), 7.53(m, 2H), 7.28 (m, 2H), 7.15(m, 2H), 6.85 (m, 3H), 6.65 (m, 1H), 5.99 (s, 2H), 5.89 (m, 1H), 4.74(m, 1H), 3.99 (m, 2H), 3.66 (m, 2H), 1.28 (d, J = 6.3 Hz, 6H) 1.10 (m,3H). LC-MS m/z = 640.4 [C30H30N3O9PS + H]⁺; Anal Calcd for(C30H30N3O9PS + 0.4 CH2Cl2): C, 54.21; H, 4.61; N, 6.24. Found; C,54.10: H, 4.49; N, 6.20. 192

654.6 (+) 12.67 (s, 1H), 7.83(m, 2H), 7.53(m, 2H), 7.29 (m, 2H), 7.15(m, 2H), 6.83 (m, 3H), 6.65 (m, 1H), 5.99 (s, 2H), 5.92 (m, 1H), 4.74(m, 1H), 3.92 (m, 3H), 1.28 (d, J = 6.3 Hz, 6H) 1.17(m, 3H), 1.02 (m,3H). Anal Calcd for (C31H32N3O9PS + 0.1 CH2Cl2): C, 56.41: H, 4.90: N,6.35. Found: C, 56.19; H, 4.92; N, 6.26. 193

682.6 (+) 12.66 (s, 1H), 7.84 (m, 2H), 7.52(m, 2H), 7.27 (m, 2H), 7.17(m, 2H), 6.82 (m, 3H), 6.65 (m, 1H), 5.98 (s, 2H), 5.79 (m, 1H), 4.73(m, 1H), 3.94 (m, 2H), 3.56 (m, 1H), 1.86 (m, 1H), 1.27 (d, J = 6.3 Hz,6H), 1.02 (m, 3H), 0.71 (m, 6H). Anal Calcd for (C33H36N3O9PS): C,58.14; H, 5.32; N, 6.16. Found: C, 58.13; H, 5.39; N, 5.88. 194

668.4 (+) 12.66 (s, 1H), 7.84(m, 2H), 7.53(m, 2H), 7.28 (m, 2H), 7.15(m, 2H), 6.81 (m, 3H), 6.60 (m, 1H), 5.98 (s, 2H), 5.74 (m, 1H), 4.73(m, 1H), 3.97 (m, 2H), 1.28 (m, 12H), 1.02 (m, 3H). Anal Calcd for(C32H34N3O9PS): C, 57.57; H, 5.13; N, 6.28. Found: C, 57.28; H, 5.05; N,6.08. 195

696.4 (+) 12.67 (s, 1H), 7.83 (m, 2H), 7.52(m, 2H), 7.27 (m, 2H), 7.17(m, 2H), 6.83 (m, 3H), 6.64 (m, 1H), 5.98 (s, 2H), 5.86 (m, 1H), 4.74(m, 1H), 3.86 (m, 2H), 3.78 (m, 1H), 1.28 (d, J = 6.0 Hz, 6H), 1.04 (m,6H), 0.72 (m, 5H). Anal Calcd for (C.34H38N3O9PS): C, 58.70; H, 5.51; N,6.04. Found: C, 58.45; H, 5.63; N, 5.78. 196

624.6 (+) 12.67 (s, 1H), 7.86 (m, 2H), 7.52 (m, 2H), 7.33 (m, 4H), 7.17(m, 4H), 6.85 (m, 1H), 5.84 (d, J = 11.4 Hz, 1H), 4.73 (m, 1H), 3.92 (m,2H), 1.30 (m, 12H), 1.03 (m, 3H). Anal Calcd for (C31H34N3O7PS + 3.2H2O + 0.1 EtOAc): C, 54.65; H, 6.02; N, 6.17. Found: C, 54.34; H, 5.23;N, 5.94. 197

663.9 (+) 8.95 (s, 1 H), 8.66-8.69 (m, 1 H), 8.47-8.51 (m, 1 H), 8.11(ddd, J = 13, 8, 2 Hz, 1 H), 7.01-7.03 (m, 2 H), 6.64 (m, 1 H),5.72-5.81 (m, 4 H), 4.58- 4.66 (m, 1 H), 3.87 (d, J = 7 Hz, 2 H),2.32-2.42 (m, 1 H), 1.64- 1.88 (m, 2 H), 1.54-1.63 (m, 4 H), 1.35 (d, J= 6 Hz, 6 H), 1.30-1.45 (m, 2H), 1.15 (s, 18 H). Anal Calcd for(C33H47N2O10P): C, 59.81; H, 7.15; N, 4.23. Found; C, 59.98; H, 7.07; N,4.01. 198

691.3 (+) 8.91 (s, 1 H), 8.68 (dd, J = 7, 2 Hz, 1 H), 8.48 (dd, J = 9, 3Hz, 1 H), 8.11 (ddd, J = 13, 9, 2 Hz, 1 H), 7.17-7.19 (m, 1 H), 7.03-7.05 (m, 2 H), 6.92-6.97 (m, 2 H), 6.66 (m, 1 H), 5.72-5.81 (m, 4 H),4.58-4.66 (m, 1 H), 4.24 (m, 2 H), 3.33 (m, 2 H), 1.35 (d, J = 5 Hz, 6H), 1.15 (s, 18 H). Anal Calcd for (C33H43N2O10PS + 1.0 H2O): C, 55.92;H, 6.40: N, 3.95. Found: C, 55.76; H, 6.02; N, 4.09. 199

547.3 (+) 8.68-8.72 (m, 2 H), 8.48 (dd, J = 9, 2 Hz, 1 H), 8.10 (ddd, J= 11, 9, 2 Hz, 1 H), 7.00 (m, 2 H), 6.64 (m, 1 H), 5.64-5.74 (m, 2 H),4.57-4.65 (m, 1 H), 3.85 (d, J = 7 Hz, 2 H), 2.32-2.39 (m, 1 H),1.80-1.87 (m, 2 H), 1.77 (d, J = 12 Hz, 3 H), 1.55-1.70 (m, 4 H), 1.35(d, J = 6 Hz, 6 H), 1.30-1.41 (m, 2 H), 1.09 (s, 9 H). Anal Calcd for(C28H39N2O7P + 1.5 H2O): C, 58.63; H, 7.38; N, 4.88. Found: C, 58.51; H,7.26; N, 5.01. 200

560.3 (+) 8.72-8.75 (m, 2 H), 8.44-8.47 (m, 1 H), 8.10-8.17 (m, 1 H),6.99-7.26 (m, 2 H), 6.63-6.64 (m, 1 H), 4.98-5.06 (m, 1 H), 4.57-4.65(m, 1 H), 3.85-3.90 (m, 1 H), 3.86 (d, J = 7 Hz, 2 H), 2.34-2.39 (m, 1H), 1.71- 1.87 (m, 2 H), 1.68 (d, J = 14 Hz, 3 H), 1.56-1.66 (m, 7 H),1.35 (d, J = 6 Hz, 6 H), 1.31- 1.41 (m, 5 H), 1.23-1.29 (m, 6 H). AnalCalcd for (C29H42N3O6P + 1.0 H2O): C, 60.30; H, 7.68; N, 7.27. Found: C,60.48; H, 7.64; N, 7.45. 201

 613.2, 615.2 (+) 11.23 (s, 1 H), 8.82 (d, J = 7 Hz, 1 H), 8.30-8.42 (m,2 H), 7.54 (m, 1 H), 7.51 (dd, J = 5, 3 Hz, 1 H), 7.45 (m, 3 H), 7.35(m, 1 H), 7.25 (m, 1 H), 7.20 (m, 1 H), 7.15 (dd, J = 2, 1 Hz, 1 H),6.72 (m, 1 H), 5.86 (m, 1 H), 4.70-4.79 (m, 2 H), 4.40-4.56 (m, 2 H),4.29 (m, 2 H), 3.09 (m, 2 H), 2.18-2.23 (m, 1 H), 1.90-1.95 (m, 1 H),1.30 (d, J = 6 Hz, 6 H). Anal Calcd for (C30H30ClN2O6PS + 0.6 H2O): C,57.76; H, 5.04; N, 4,49. Found: C, 57.88; H, 5.04; N, 4.37. 202

535.3 (+) 11.18 (s, 1 H), 8.70-8.73 (m, 1 H), 8.32-8.36 (m, 1 H), 8.14-8.22 (m, 1 H), 7.20 (s, 2 H), 6.68 (m, 1 H), 5.57-5.63 (m, 2 H),4.71-4.79 (m, 1 H), 4.08 (q, J = 7 Hz, 2 H), 3.93 (d, J = 7 Hz, 2 H),2.28-2.38 (m, 1 H), 1.86 (d, J = 15 Hz, 3 H), 1.75- 1.83 (m, 2 H),1.52-1.67 (m, 4 H), 1.30(d, J = 6 Hz, 6 H), 1.29-1.40 (m, 2 H), 1.16 (t,J = 7 Hz, 3 H). Anal Calcd for (C26H35N2O8P + 0.4 H2O): C, 57.64; H,6.66; N, 5.17. Found: C, 57.31; H, 6.27; N, 5.06. 203

661.3 (+) 8.76 (m, 1 H), 8.61 (m, 1 H), 8.29 (m, 1 H), 7.31-7.34 (m, 2H0, 7.15 (s, 2 H), 7.09 (d, J = 5 Hz, 1 H), 6.69 (m, 1 H), 4.64- 4.72(m, 1 H), 4.08-4.28 (m, 5 H), 3.99-4.04 (m, 1 H), 3.60- 3.63 (m, 1 H),3.34-3.38 (m, 1 H), 3.18 (m, 2 H), 1.44-1.49 (m, 6 H), 1.39 (d, J = 6Hz, 6 H), 1.21-1.35 (m, 6 H). Anal Calcd for (C31H41N4O8PS + 0.4 H2O):C, 55-75; H, 6.31; N, 8.39. Found: C, 55.87; H, 6.61; N, 8.65. 204

585.4 (+) 12.66 (s, 1 H), 7.91 (dd, J = 13, 9 Hz, 2 H), 7.52-7.54 (m, 2H), 7.47 (m, 1 H), 7.37-7.42 (m, 2 H), 7.27 (m, 1 H), 7.19 (dd, J = 9, 4Hz, 2 H), 6.94 (m, 1 H), 5.77-5.80 (m, 1 H), 4.63-4.79 (m, 3 H),4.35-3.45 (m, 1 H), 2.30-2.40 (m, 1 H), 2.13-2.17 (m, 1 H), 1.29 (d, J =6 Hz, 6 H). Anal Calcd for (C28H26ClN2O8PS + 0.1 EtOAc + 0.1 CH2Cl2): C,56.83; H, 4.52; N, 4.65. Found: C, 56.90; H, 4.89: N, 4.37. 205

552.6 (+) 8.58 (m, 2 H), 7.91 (dd, J = 13, 9 Hz, 2 H), 7.53-7.54 (m, 2H), 7.37-7.41 (m, 3 H), 7.27 (d. J = 4 Hz, 1 H), 7.19 (dd, J = 9, 2 Hz,2 H), 6.94 (m, 1 H), 5.80- 5.84 (m, 1 H), 4.65-4.80 (m, 2H), 4.37-4.47(m, 1 H), 2.24- 2.30 (m, 2 H), 1.29 (d, J = 6 Hz, 6 H). Anal Calcd for(C27H26N3O6PS + 0.2 CH2Cl2): C, 57.46; H, 4.68; N, 7.39. Found: C,57.12; H, 4.79; N, 7.18. 206

633.6 (+) 7.76 (dd, J = 12, 9 Hz, 2 H), 7.56 (d, J = 4 Hz, 1 H), 7.52(m, 1 H), 7.26-7.29 (m, 2 H), 7.14 (dd, J = 9, 2 Hz, 2 H), 6.82 (m, 1H), 4.90 (m, 1 H), 4.70-4.77 (m, 2 H), 3.93-4.09 (m, 4 H), 3.79-3.85 (m,2 H), 1.30 (d, J = 6 Hz, 6 H), 1.06-1.27 (m, 12 H). Anal Calcd for(C29H37N4O8PS): C, 55.05; H, 5.89; N, 8.86. Found: C, 54.89; H, 6.16; N,8.71. 207

661.9 (+) 7.76 (dd, J = 12, 9 Hz, 2 H), 7.56 (d, J = 4 Hz, 1 H), 7.53(m, 1 H), 7.28-7.29 (m, 2 H), 7.34 (dd, J = 9, 2 Hz, 2 H), 6.82 (m, 1H), 4.76 (m, 1 H), 4.63 (d, J = 11 Hz, 2 H), 4.03 (q, J = 7 Hz, 4 H),1.41 (s, 3 H), 1.33 (s, 3 H), 1.30 (d, J = 6 Hz, 6 H), 1.16 (t, J = 7Hz, 12 H). Anal Calcd for (C31H41N4O8PS + 0.1 HCl + 0.80 H2O): C, 52.32;H, 6.18; N, 7.87. Found: C, 52.02; H, 5.84; N, 8.27. 208

689.9 (+) 7.76 (dd, J = 12, 9 Hz, 2 H), 7.54 (d, J = 4 Hz, 1 H), 7.51(m, 1 H), 7.26-7.27 (m, 2 H), 7.11 (dd, J = 9, 2 Hz, 2 H), 6.79 (m, 1H), 4.76 (m, 1 H), 4.83 (m, 2 H), 4.74 (m, 1 H), 4.58 (d, J = 11 Hz, 2H), 1.29 (d, J = 6 Hz, 6 H), 1.17 (s, 6 H), 1.16 (d, J = 6 Hz, 12 H).Anal Calcd for (C33H45N4O8PS − 0.5 H2O): C, 56.80; H, 6,64; N, 8.03.Found: C, 56.82; H, 6.53; N, 8.01. 209

605.9 (+) 7.77 (dd, J = 12, 9 Hz, 2 H), 7.54 (d, J = 4 Hz, 1 H), 7.51(m, 1 H), 7.26-7.27 (m, 2 H), 7.13 (dd, J = 9, 2 Hz, 2 H), 6.82 (m, 1H), 4.74-4.83 (m, 3 H), 4.04 (q, J = 7 Hz, 4 H), 3.56-3.65 (m, 4 H),1.29 (d, J = 6 Hz, 6 H), 1.14 (t, J = 7 Hz, 12 H). Anal Calcd for(C27H33N4O8PS): C, 53.64; H. 5.50; N, 9.27. Found: C, 53.42; H, 5.41; N,9.08. 210

718.1 (+) 7.74 (dd, J = 12, 9 Hz, 2 H), 7.53 (d, J = 4 Hz, 1 H), 7.49(m, 1 H), 7.26 (d, J = 4 Hz, 1 H), 7.21 (m, 1 H), 7.12 (dd, J = 9, 2 Hz,2 H), 6.74 (m, 1 H), 4.71- 4.81 (m, 2 H), 4.49 (m, 1 H), 4.06 (m, 2 H),3.88 (m, 2 H), 3.72 (m, 2 H), 1.29-1.73 (m, 6 H), 1.28 (d, J = 6 Hz, 6H), 1.18 (m, 3 H), 1.00 (m, 3 H), 0.72- 0.88 (m, 12 H). Anal Calcd for(C35H49N4O8PS): C, 58.64; H, 6.89: N, 7.82. Found: C, 58.84; H, 6.98; N,7.53. 211

690.1 (+) 7.73 (dd, J = 12, 9 Hz, 2 H), 7.54 (d, J = 4 Hz, 1 H), 7.50(m, 1 H), 7.27 (d, J = 4 Hz, 1 H), 7.23 (m, 1 H), 7.11 (dd, J = 9, 2 Hz,2 H), 6.77 (m, 1 H), 4.73 (m, 1 H), 4.61 (m, 1 H), 4.45 (m, 1 H),4.03-4.14 (m, 2 H), 3.83-3.95 (m, 2 H), 3.52-3.60 (m, 1 H), 3.35-3.44(m, 1 H), 1.90 (m, 2 H), 1.28 (d, J = 6 Hz, 6 H), 1.18 (t, 3 H), 1.02(t, 3 H), 0.89 (t, 6 H), 0.77 (t, 6 H). Anal Calcd for (C33H45N4O8PS +1.0 HCl, + 0.7 H2O); C, 53.72; H, 6.48; N, 7.58. Found: C, 53.63; H,6.23; N, 7.58. 212

695.4 (+) 7.73 (dd, J = 12, 7 Hz, 2 H), 7.54 (m, 2 H), 7.35 (m, 1 H),7.27 (d, J = 4 Hz, 1 H), 7.17 (dd, J = 7, 2 Hz, 2 H), 6.89 (m, 1 H),5.67 (m, 4 H), 4.75 (m, 1 H), 3.87 (d, J = 7 Hz, 4 H), 1.85 (m, 2 H),1.29 (d, J = 6 Hz, 6 H), 0.83 (d, J = 7 Hz, 6 H). Anal. Calcd. for(C₃₁H₃₉N₂O₁₂PS): C, 53.60; H, 5.66; N, 4.03. Found: C, 53.32: H, 5.69;N, 3.96.

Example 213{4-[3-(2-Fluoro-phenylcarbamoyl)-5-isopropoxy-phenoxy]-phenyl}-phosphonicacid

To a solution of3-[4-(diisopropoxy-phosphoryl)-phenoxy]-5-isopropoxy-benzoic acid(prepared as in Example 3 Step E) (530 mg, 1.2 mmol) in toluene (10 mL)was added thionyl chloride (0.22 mL, 3.0 mmol). The reaction was heatedto 110° C. for 1 h and allowed to cool to room temperature. The solventswere removed by rotary evaporation, and the crude product wasre-dissolved in toluene and treated with 2-fluoroaniline (0.11 mL, 1.2mmol), diisopropylethylamine (0.6 mL, 3.6 mmol), and catalytic DMAP. Thereaction was then heated to 110° C. for 1 hour, at which point TLCanalysis indicated that the reaction was complete. The reaction wascooled to room temperature and preloaded on silica. The desired product,{4-[3-(2-fluoro-phenylcarbamoyl)-5-isopropoxy-phenoxy]-phenyl}-phosphonicacid diisopropyl ester, (350 mg, 54%) was obtained after chromatographyon silica gel eluting with ethyl acetate in hexanes. LC-MS m/z=530[C₂H₃₃FNO₆P+H]⁺.

The above prepared{4-[3-(2-fluoro-phenylcarbamoyl)-5-isopropoxy-phenoxy]-phenyl}-phosphonicacid diisopropyl ester was converted to the title compound following theprocedure described in Example 2. ¹H NMR (300 MHz, DMSO-d₆): δ 10.11 (s,1H), 7.80-7.70 (q, 2H), 7.50 (t, 1H), 7.39 (s, 1H), 7.38-7.08 (m, 6H),6.83 (s, 1H), 4.65 (m, 1H), 1.30 (d, 6H). ³¹P NMR (300 MHz, DMSO-d₆): δ13.45. ¹⁹F NMR (300 MHz, DMSO-d₆): δ −121.25. LC-MS m/z=446[C₂₂H₂₁FN₃O₆P+H]⁺. Anal. Calcd for (C₂₂H₂₁FN₃O₆P+1.3H₂O): C, 56.37; H,5.07; N, 2.99. Found: C, 56.40; H, 4.85; N, 2.83.

Examples: Biological Examples

The assays below can be used to test compounds of the present invention.Compounds set forth in the chemistry Examples above were assayed usingthe Human Enzyme Assay below (compounds may have been tested inadditional assays as well). The compounds of the above Examples weretested in the Human Enzyme Assay at a concentration of 100 M and wereable to activate 50 &g of human glucokinase by at least 150%.

Example A. Human Enzyme Assay

Biochemical activation of GK is accomplished with assays that utilizepurified recombinant human GK (isoform 1/variant 2) and purifiedrecombinant Leuconostoc mesenteroides glucose-6-phosphate dehydrogenase(Sigma-Aldrich, Inc.). In these assays, glucose is acted upon by GK toform glucose-6-phosphate. Subsequently, glucose-6-phosphate is actedupon by glucose-6-phosphate dehydrogenase to form 6-phospho-D-gluconateand beta-NADPH, which can be quantified spectrophotometrically.Specifically, compounds are serially diluted to 100× the finalconcentration in DMSO. After dilution, 3 uL of the compound solution and277 uL of Reaction Buffer (25 mM HEPES-pH 7.4, 25 mM KCl, 2 mM MgCl₂,and 10 mM ATP, 0.5 mM beta-NADP, 1 mM DTT, 0.1% bovine serum albumin)are added to each well of a UV/Visible transparent 96-well microtiterplates (Falcon Inc.). The microtiter plates are then placed on wet icefor 10 min. The enzymatic reactions are initiated by the addition of 10uL glucose-6-phosphate dehydrogenase (˜40 ug/well) and 10 uL of GK (˜50ug/well). After initiation, the microtiter plate is immediately placedinto a microtiter plate reader (SpectraMax 190; Molecular Devices Inc.)and the generation of beta-NADPH is monitored at 340 nm for 20 min at30° C.

Example B. Rat Hepatocyte Assay

Cellular activation of OK is accomplished with assays that utilized[2-³H] glucose (G.E. Healthcare Inc.) and primary hepatocytes isolatedfrom fed adult male Sprague-Dawley rats (Harlan Inc.). All animalprocedures are conducted in accordance with the National Institutes ofHealth Guidelines for the Care and Use of Laboratory Animals and areapproved by the Institutional Animal Care and Use Committee. In theseassays, [2-³H] glucose is taken up into the hepatocytes and acted uponby endogenous GK to form [2-3H] glucose-6-phosphate. Subsequently,[2-³H] glucose-6-phosphate is acted upon by endogenous phosphoglucoseisomerase to form fructose-6-phosphate and ³H₃O⁻, which diffuses out ofthe hepatocyte into the culture media. Specifically, rats (˜300 g) areanaesthetized with pentobarbital (Savemart Inc.) administered atconcentration of 2 uL/gram body weight. After confirming no response todeep pain stimuli, the abdominal cavity is exposed. The livers areperfused at ˜25 ml/min through the portal vein with Perfusion Buffer[Krebs-Ringer bicarbonate buffer supplemented with 2.5 mM CaCl₂ and 1%fatty acid free BSA (Calbiochem Inc.)] and drained through the supravena cava during the procedure. The buffer is prepared by equilibratingat 37° C. and aerating with a 95% oxygen/S % carbon dioxide mixture.After, 2 to 3 min the Perfusion Buffer is supplemented with 1 mg/mlcollagenase (Sigma-Aldrich Inc.). Following perfusion viable cells areisolated will 70% Percoll gradient in aerated Perfusion Buffer. Afterisolation, hepatocytes are resuspended (700,000 cells/mL) in Dulbecco'sminimal essential medium (DMEM, Invitrogen Inc.) supplemented with 5.6mM glucose, 10% fetal bovine serum (FBS), 1 U/mL penicillin, 0.1 mg/mLstreptomycin, and 2 mM L-glutamine. The resuspended hepatocytes areplated 500 uL/well on a 24-well plate (Becton Dickenson Labware Inc.)and incubated at 37° C. in 95% O₂/5% CO₂ in a water-jacketed incubator(Forma Scientific Inc.). After attachment to the plate (˜2 hr), media isremoved and 500 uL of serum-free DMEM supplemented with 5.6 mM glucose,1 U/mL penicillin, 0.1 mg/mL streptomycin, and 2 mM L-glutamine isadded. After 16-20 hr, 2 uCi/mL [2-³H] glucose and compound solutionsare added to the media. Compounds are first serially diluted to 100× thefinal concentration in DMSO and are added in a 5 uL volume. After 3 hrs,500 uL of media is removed and ³H₃O⁺ is isolated by strong anionexchange chromatography using AG 1-X8 columns (Bio Rad LaboratoriesInc.) according to the manufacture's recommendations. Quantification ofthe isolated ³H₃O⁺ is accomplished by scintillation counting usingscintillation cocktail (Packard BioScience Inc.) and a scintillationcounter (LS6000IC; Palo Beckman Inc.).

Example C. Fasting Blood Glucose Test

Effects on fasting blood glucose after administration of compounds aredetermined in conscious overnight fasted male Zucker fa/fa rats (HarlanInc.) that range from 8 to 0 weeks in age. All animal procedures areconducted in accordance with the National Institutes of HealthGuidelines for the Care and Use of Laboratory Animals and are approvedby the Institutional Animal Care and Use Committee. Whole blood glucoselevels are determined by a glucose meter (OneTouch Ultra, Life ScanInc.) and whole blood is collected by a tail vein nick method. Prior toadministration, compounds are formulated in phosphate buffered saline pH˜7.4 (PBS). Before and after administration of either compoundformulation or PBS, glucose levels are measured at regular timeintervals.

Example D. Oral Glucose Tolerance Test (OGTT)

Effects on OGTT after administration of compounds are determined inconscious overnight fasted male Zucker fa/fa rats (Harlan Inc.) thatrange from 8 to 20 weeks in age. All animal procedures are conducted inaccordance with the National Institutes of Health Guidelines for theCare and Use of Laboratory Animals and are approved by the InstitutionalAnimal Care and Use Committee. Whole blood glucose levels are determinedby a glucose meter (OneTouch Ultra, Life Scan Inc.) and whole blood isisolated by a tail vein nick method. Prior to administration, compoundsare formulated in phosphate buffered saline pH˜7.4 (PBS). Thirty minafter administration of either compound formulation or PBS, an aqueoussolution of D-glucose is orally administered at dosage of 2 g/kg bodyweight. Before and after administration of either compound formulationor PBS, blood samples for glucose and insulin levels determinations arecollected at regular time intervals.

Example D. Insulin Secretion Test

Effects on insulin secretion after administration of compound isdetermined in conscious overnight fasted adult male Sprague-Dawley(Harlan Inc.) rats that are cannulated through the jugular vein. Allanimal procedures are conducted in accordance with the NationalInstitutes of Health Guidelines for the Care and Use of LaboratoryAnimals and are approved by the Institutional Animal Care and UseCommittee. Whole blood glucose levels are determined by a glucose meter(OneTouch Ultra, Life Scan Inc.) and whole blood is isolated from thecannula. Plasma is isolated from whole blood by centrifugation inHeparinized plasma separator tubes (BD Microtainer Inc.) and plasmainsulin levels are determined by insulin specific radioimmunoassaydetection (Linco Inc.). Prior to administration, compounds areformulated in phosphate buffered saline pH ˜7.4 (PBS). Before and afteradministration of either compound formulation or PBS, glucose andinsulin levels are measured at regular time intervals.

1. A compound of Formula (II),

wherein: X is selected from the group consisting of aryl, heteroaryl,alkyl, cycloalkyl, arylalkyl, aryloxy, heteroaryloxy, alkyloxy,cycloalkyloxy, and arylalkyloxy, and G² is CR⁴ or N, or together G² andX are connected to form a cyclic group containing 5-7 atoms, wherein 0-2atoms of said cyclic group are heteroatoms and the remaining atoms ofsaid cyclic group are carbon atoms substituted with alkyl, aryl,cycloalkyl or heteroaryl; R² is optionally substituted and is selectedfrom alkylene, cycloalkylene, arylene-O—, heteroarylene-O—,arylalkylene-O—, alkylarylene-O—, arylene-S—, heteroarylene-S—,alkylene-S—, cycloalkylene-S—, arylalkylene-S—, or alkylarylene-S—,wherein R² is connected to R⁵⁰ by a carbon atom; G¹ is CR⁴ or N; R⁴ isH, halogen, or optionally substituted alkyl; G³ is CR⁴ or N; R⁴ is H,halogen, or optionally substituted alkyl; D is selected from a groupconsisting of heteroaryl, aryl, optionally substituted heteroaryl, andoptionally substituted aryl; R⁵⁰ is —P(O)(Y²R⁵¹) R¹ or —P(O)(YR⁵¹)Y¹R⁵¹;R¹ is selected from the group consisting of hydrogen, optionallysubstituted —C₁-C₆-alkyl, —CF₃, —CHF₂, —CH₂F, —CH₂OH, optionallysubstituted —C₂-C₆ alkenyl, optionally substituted —C₂-C₆ alkynyl,optionally substituted —(CR⁵² ₂)_(n)cycloalkyl, optionally substituted(CR⁵² ₂)_(n)heterocycloalkyl, —(CR⁵² ₂)_(k) S(═O)R⁵³, and —(CR⁵²₂)_(k)S(═O)₂R⁵³; Y, Y¹, and Y² are each independently selected from —O—or —NR⁶⁰; wherein, when Y² is —O— or when Y and Y¹ are both —O—, R⁵¹attached to —O— is independently selected from —H, alkyl, optionallysubstituted aryl, optionally substituted heterocycloalkyl, optionallysubstituted —CH₂-heterocycloakyl wherein the cyclic moiety contains acarbonate or thiocarbonate, optionally substituted -alkylaryl,—C(R⁵²)₂OC(O)NR⁵² ₂, —NR⁵²—C(O)—R⁵³, —C(R⁵²)₂—OC(O)R⁵³,—C(R⁵²)₂—O—C(O)OR⁵³, —C(R⁵²)₂OC(O)SR⁵³, -alkyl-S—C(O)R⁵³,-alkyl-S—S-alkylhydroxy, and -alkyl-S—S—S-alkylhydroxy; or when Y² is—NR⁶⁰— or when Y and Y¹ are both —NR⁶⁰—, then R⁵¹ attached to —NR⁶⁰ isindependently selected from —H, —[C(R⁵²)₂]_(r)—COOR⁵³, —C(R⁵⁴)₂COOR⁵³,—[C(R⁵²)₂]_(r)—C(O)SR⁵³, and -cycloalkylene-COOR⁵³; or when Y is —O— andY¹ is NR⁶⁰, then R⁵¹ attached to —O— is independently selected from —H,alkyl, optionally substituted aryl, optionally substitutedheterocycloalkyl, optionally substituted CH₂-heterocycloakyl wherein thecyclic moiety contains a carbonate or thiocarbonate, optionallysubstituted -alkylaryl, —C(R⁵²)₂OC(O)NR⁵² ₂, —NR⁵²—C(O)—R⁵³,—C(R⁵²)₂—OC(O)R⁵³, —C(R⁵²)₂—O—C(O)OR⁵³, —C(R⁵²)₂OC(O)SR⁵³,-alkyl-S—C(O)R⁵³, -alkyl-S—S-alkylhydroxy, and-alkyl-S—S—S-alkylhydroxy, and R⁵¹ attached to —NR⁶⁰— is independentlyselected from —H, —[C(R⁵²)₂]_(r)—COOR⁵³, —C(R⁵⁴)₂COOR⁵³,—[C(R⁵²)₂]_(r)—C(O)SR⁵³, and -cycloalkylene-COOR⁵³, wherein if both R⁵¹are alkyl, at least one is higher alkyl; or when Y and Y¹ areindependently selected from —O— and —NR⁶⁰—, then R⁵¹ and R⁵¹ togetherform a cyclic group comprising -alkyl-S—S-alkyl-, or R⁵¹ and R⁵¹together are the group

wherein, V, W, and W′ are independently selected from the groupconsisting of hydrogen, optionally substituted alkyl, optionallysubstituted aralkyl, heterocycloalkyl, aryl, substituted aryl,heteroaryl, substituted heteroaryl, optionally substituted 1-alkenyl,and optionally substituted 1-alkynyl; and Z is —CHR⁵²OH, —CHR⁵²OC(O)R⁵³,—CHR⁵²OC(S)R⁵³, —CHR⁵²OC(S)OR⁵³, —CHR⁵²OC(O)SR⁵³, —CHR⁵²OCO₂R⁵³, —OR⁵²,—SR⁵², —CHR⁵²N₃, —CH₂aryl, —CH(aryl)OH, —CH(CH═CR⁵² ₂)OH, —CH(C═CR⁵²)OH,—R⁵², —NR⁵² ₂, —OCOR⁵³, —OCO₂R⁵³, —SCOR⁵³, —SCO₂R⁵³, —NHCOR⁵²,—NHCO₂R⁵³, —CH₂NHaryl, —(CH₂)r-OR⁵² or —(CH₂)_(r)—SR⁵²; or W and W′ areas defined above and together V and Z are connected via an additional3-5 atoms to form a cyclic group containing 5-7 atoms, wherein 0-1 atomsare heteroatoms and the remaining atoms are carbon; or W′ and Z are asdefined above and together V and W are connected via an additional 3carbon atoms to form an optionally substituted cyclic group containing 6carbon atoms or carbon substituted by hydrogen and substituted with onesubstituent selected from hydroxy, acyloxy, alkoxycarbonyloxy,alkylthiocarbonyloxy or aryloxycarbonyloxy which is attached to one ofsaid carbon atoms that is three atoms from a Y attached to thephosphorus; or V and W′ are as defined above and together Z and W areconnected via an additional 3-5 atoms to form a cyclic group, wherein0-1 atoms are heteroatoms and the remaining atoms are carbon or carbonsubstituted by hydrogen, and V must be aryl, substituted aryl,heteroaryl, or substituted heteroaryl; or V and Z are as defined aboveand together W and W′ are connected via an additional 2-5 atoms to forma cyclic group, wherein 0-2 atoms are heteroatoms and the remainingatoms are carbon, where V must be aryl, substituted aryl, heteroaryl, orsubstituted heteroaryl; R⁵² is R⁵³ or —H; R⁵³ is alkyl, aryl,heterocycloalkyl or aralkyl; R⁵⁴ is independently selected from —H oralkyl, or together R⁵⁴ and R⁵⁴ form a cycloalkylene group; R⁶⁰ is —H,lower alkyl, acyloxyalkyl, alkoxycarbonyloxyalkyl, lower acyl,C₁₋₆-perfluoroalkyl or NH(CR⁵⁵R⁵⁵)_(f)CH₃; r is an integer 2 or 3; f isan integer 0, 1, or 2; wherein, V, Z, W, W′ are not all —H, and when Zis —R⁵², then at least one of V, W, and W′ is not —H, alkyl, aralkyl, orheterocycloalkyl; and pharmaceutically acceptable salt thereof.
 2. Thecompound of claim 1, wherein X is selected from the group consisting ofalkyl, cycloalkyl, alkyloxy, cycloalkyloxy, and aryloxy.
 3. The compoundof claim 1, wherein X is selected from the group consisting of alkyloxyand cycloalkyloxy.
 4. The compound of claim 1, wherein X is selectedfrom the group consisting of aryl, heteroaryl, alkyl, cycloalkyl,arylalkyl, aryloxy, heteroaryloxy, alkyloxy, cycloalkyloxy, andarylalkyloxy.
 5. The compound of claim 1, wherein R² is -E¹-E²-E³-E⁴-,wherein E⁴ is connected to R⁵⁰; E¹ is O or S; E² is alkylene; E³ isoptionally substituted propyl, butyl, tert butyl, optionally substitutedC₃₋₈-cycloalkylalkylene, arylene or heteroarylene optionally substitutedwith one or two groups independently selected from aryl, heteroaryl,cycloalkyl, cycloalkenyl, halogen, CN, CF₃, NR⁵ ₂, —C₁₋₄-alkyl,—S(O)₂R⁵, or —OR⁵; R⁵ is optionally substituted alkyl or cycloalkyl; andE⁴ is a bond or alkylene.
 6. The compound of claim 1, wherein R² isselected from the group consisting of phenylene-O—,methylene-phenylene-O—, phenylene-methylene-O—, furan-2-yl-5-methylene,thiophen-2-yl-5-methylene, pyridin-diyl-O—, pyrimidin-diyl-O—,pyridazin-diyl-O— and pyrazin-diyl-O—, each optionally substituted withone or two groups independently selected from aryl, heteroaryl, halogen,CN, CF₃, NR⁵ ₂, —C₁₋₄-alkyl, —S(O)₂R⁵, or —OR⁵, wherein R⁵⁰ is connectedto R² by a carbon atom.
 7. The compound of claim 1, wherein R² isphenylene-O— or thiophen-2-yl-5-methylene, wherein R⁵⁰ is connected tothe phenylene or thiophenyl group.
 8. The compound of claim 1, whereinR² is optionally substituted and is selected from alkylene,cycloalkylene, arylene-O—, heteroarylene-O—, arylalkylene-O—,alkylarylene-O—, arylene-S—, heteroarylene-S—, alkylene-S—,cycloalkylene-S—, arylalkylene-S—, or alkylarylene-S—, wherein R⁵⁰ isconnected to R² by a carbon atom.
 9. The compound of claim 1, wherein G¹and G² are CR⁴ or N.
 10. The compound of claim 1, wherein G¹ and G² areCR⁴ and R⁴ is H, halogen or optionally substituted alkyl.
 11. Thecompound of claim 10, wherein R⁴ is H.
 12. The compound of claim 1,wherein G³ is CR⁴ or N.
 13. The compound of claim 1, wherein G³ is CR⁴and R⁴ is H, halogen or optionally substituted alkyl.
 14. The compoundof claim 1, wherein R⁴ is H.
 15. The compound of claim 1, wherein D isselected from a group consisting of heteroaryl and aryl.
 16. Thecompound of claim 1, wherein D is a heteroaryl having a nitrogen as aring atom, said heteroaryl comprising a nitrogen ring atom adjacent to acarbon ring atom, wherein said carbon ring atom is connected to theamide nitrogen atom adjacent to D, and wherein said heteroaryl has anadditional 0 to 3 heteroatoms independently selected from O, S or N. 17.The compound of claim 1, wherein D is selected from the group consistingof pyridinyl, thiazolyl, 1,3,4-thiadiazolyl, 1,2,4-thiadiazolyl,oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, pyrazinyl, pyridazinyl,pyrimidinyl, benzothiazolyl, and 5,6-dihydro-4H-cyclopentathiazolyl,each optionally substituted with one or two groups selected fromhalogen, CF₃, or optionally substituted C₁₋₄-alkyl.
 18. The compound ofclaim 1, wherein D is selected from the group consisting of thiazolyl,1,3,4-thiadiazolyl, and 1,2,4-thiadiazolyl, each optionally substitutedwith one or two groups selected from halogen, CF₃, or optionallysubstituted C₁₋₄-alkyl.
 19. The compound of claim 1, wherein R⁵⁰ is—P(O)(Y²R⁵¹) R¹ or —P(O)(YR⁵¹)Y¹R⁵¹; R¹ is selected from the groupconsisting of hydrogen, optionally substituted —C₁-C₆-alkyl, —CF₃,—CHF₂, —CH₂F, —CH₂OH, optionally substituted —C₂-C₆ alkenyl, optionallysubstituted —C₂-C₆ alkynyl, optionally substituted —(CR⁵²₂)_(n)cycloalkyl, optionally substituted (CR⁵² ₂)_(n)heterocycloalkyl,—(CR⁵² ₂)_(k)S(═O)R⁵³, and —(CR⁵² ₂)_(k)S(═O)₂R⁵³; Y, Y¹ and Y² are eachindependently selected from —O— or —NR⁶⁰—; wherein, when Y² is —O— orwhen Y and Y¹ are both —O—, R⁵¹ attached to —O— is independentlyselected from —H, alkyl, optionally substituted aryl, optionallysubstituted heterocycloalkyl, optionally substituted—CH₂-heterocycloakyl wherein the cyclic moiety contains a carbonate orthiocarbonate, optionally substituted -alkylaryl, —C(R⁵²)₂OC(O)NR⁵² ₂,—NR⁵²—C(O)—R⁵³, —C(R⁵²)₂—OC(O)R⁵³, —C(R⁵²)₂—O—C(O)OR⁵³,—C(R⁵²)₂OC(O)SR⁵³, -alkyl-S—C(O)R⁵³, -alkyl-S—S-alkylhydroxy, and-alkyl-S—S—S-alkylhydroxy; when Y² is —NR⁶⁰— or when Y and Y¹ are both—NR⁶⁰—, then R⁵¹ attached to —NR⁶⁰— is independently selected from —H,—[C(R⁵²)₂]_(r)—COOR⁵³, —C(R⁵⁴)₂COOR⁵³, —[C(R⁵²)₂]_(r)—C(O)SR⁵³, and-cycloalkylene-COOR⁵³; or when Y is —O— and Y¹ is NR⁶⁰, then R⁵¹attached to —O— is independently selected from —H, alkyl, optionallysubstituted aryl, optionally substituted heterocycloalkyl, optionallysubstituted CH₂-heterocycloakyl wherein the cyclic moiety contains acarbonate or thiocarbonate, optionally substituted -alkylaryl,—C(R⁵²)₂OC(O)NR⁵² ₂, —NR⁵²—C(O)—R⁵³, —C(R⁵²)₂—OC(O)R⁵³,—C(R⁵²)₂—O—C(O)OR⁵³, —C(R⁵²)₂OC(O)SR⁵³, -alkyl-S—C(O)R⁵³,-alkyl-S—S-alkylhydroxy, and -alkyl-S—S—S-alkylhydroxy, and R⁵¹ attachedto —NR⁶⁰— is independently selected from —H, —[C(R⁵²)₂]_(r)—COOR⁵³,—C(R⁵⁴)₂COOR⁵³, —[C(R⁵⁴)₂]_(r)—C(O)SR⁵³, and -cycloalkylene-COOR⁵³,wherein if both R⁵¹ are alkyl, at least one is higher alkyl; or when Yand Y¹ are independently selected from —O— and —NR⁶⁰—, then R⁵¹ and R⁵¹together form a cyclic group comprising -alkyl-S—S-alkyl-, or R⁵¹ andR⁵¹ together are the group

wherein, V, W, and W′ are independently selected from the groupconsisting of hydrogen, optionally substituted alkyl, optionallysubstituted aralkyl, heterocycloalkyl, aryl, substituted aryl,heteroaryl, substituted heteroaryl, optionally substituted 1-alkenyl,and optionally substituted 1-alkynyl; and Z is —CHR⁵²OH, —CHR⁵²OC(O)R⁵³,—CHR⁵²OC(S)R⁵³, —CHR⁵²OC(S)OR⁵³, —CHR⁵²OC(O)SR⁵³, —CHR⁵²OCO₂R⁵³, —OR⁵²,—SR⁵², —CHR⁵²N₃, —CH₂aryl, —CH(aryl)OH, —CH(CH═CR⁵² ₂)OH, —CH(C═CR⁵²)OH,—R⁵², —NR⁵² ₂, —OCOR⁵³, —OCO₂R⁵³, —SCOR⁵³, —SCO₂R⁵³, —NHCOR⁵²,—NHCO₂R⁵³, —CH₂NHaryl, —(CH₂)r-OR⁵² or —(CH₂)_(r)—SR⁵²; or W and W′ areas defined above and together V and Z are connected via an additional3-5 atoms to form a cyclic group containing 5-7 atoms, wherein 0-1 atomsare heteroatoms and the remaining atoms are carbon; or W′ and Z are asdefined above and together V and W are connected via an additional 3carbon atoms to form an optionally substituted cyclic group containing 6carbon atoms or carbon substituted by hydrogen and substituted with onesubstituent selected from hydroxy, acyloxy, alkoxycarbonyloxy,alkylthiocarbonyloxy or aryloxycarbonyloxy which is attached to one ofsaid carbon atoms that is three atoms from a Y attached to thephosphorus; or V and W′ are as defined above and together Z and W areconnected via an additional 3-5 atoms to form a cyclic group, wherein0-1 atoms are heteroatoms and the remaining atoms are carbon or carbonsubstituted by hydrogen, and V must be aryl, substituted aryl,heteroaryl, or substituted heteroaryl; or V and Z are as defined aboveand together Wand W′ are connected via an additional 2-5 atoms to form acyclic group, wherein 0-2 atoms are heteroatoms and the remaining atomsare carbon, where V must be aryl, substituted aryl, heteroaryl, orsubstituted heteroaryl; R⁵² is R⁵³ or —H; R⁵³ is alkyl, aryl,heterocycloalkyl or aralkyl; R⁵⁴ is independently selected from —H oralkyl, or together R⁵⁴ and R⁵⁴ form a cycloalkylene group; R⁶⁰ is —H,lower alkyl, acyloxyalkyl, alkoxycarbonyloxyalkyl, lower acyl,C₁₋₆-perfluoroalkyl or NH(CR⁵⁵R⁵⁵)_(f)CH₃; r is an integer 2 or 3; f isan integer 0, 1, or 2; wherein, V, Z, W, W′ are not all —H, and when Zis —R⁵², then at least one of V, W, and W′ is not —H, alkyl, aralkyl, orheterocycloalkyl; and pharmaceutically acceptable salt thereof.
 20. Thecompound of claim 1, wherein R⁵⁰ is selected from the group consistingof —PO₃H₂, —P(O)[—OCR⁵² ₂OC(O)R⁵³]₂, —P(O)[—OCR⁵² ₂OC(O)OR⁵³]₂,—P(O)[—N(H)CR⁵² ₂C(O)OR⁵³]₂, —P(O)[—O-alk-SC(O)R⁵³]₂, —P(O)[—OCR⁵²₂OC(O)R⁵³][—R¹], —P(O)[—OCR⁵² ₂OC(O)OR⁵³][—R¹], —P(O)[—N(H)CR⁵²₂C(O)OR⁵³][—R¹], —P(O)[—OCH₂CH₂SC(O)R⁵³][—R¹], —P(O)(OH)(YR⁵¹),—P(O)(OR⁵⁶)(OR⁵⁶), —P(O)(OH)(—R¹—P(O)[—OCR⁵² ₂OC(O)R⁵³](OR⁵⁶),—P(O)[—OCR⁵² ₂OC(O)OR⁵³](OR⁵⁶), —P(O)[—N(H)CR⁵² ₂C(O)OR⁵³](OR⁵⁶),P(O)(OH)(NH₂), and P(O)[—OCH(V)CH₂CH₂O—]; V is optionally substitutedaryl or optionally substituted heteroaryl; R⁵⁶ is —C₁-C₁₂ alkyl, —C₂-C₁₂alkenyl, —C₂-C₁₂ alkynyl, —(CR⁵⁷ ₂)_(n)aryl, —CR⁵²)_(n)cycloalkyl, or—(CR⁵⁷ ₂)_(n)heterocycloalkyl, each optionally substituted; each R⁵⁷ isindependently selected from the group consisting of hydrogen, optionallysubstituted —C₁-C₄ alkyl, halogen, optionally substituted —O—C₁-C₄alkyl, —OCF₃, optionally substituted —S—C₁-C₄ alkyl, —NR⁵⁸R⁵⁹,optionally substituted —C₂-C₄ alkenyl, and optionally substituted —C₂-C₄alkynyl; with the proviso that when one R⁵⁷ is attached to C through an0, S, or N atom, then the other R⁵⁷ attached to the same C is ahydrogen, or attached via a carbon atom; R⁵⁸ is selected from hydrogenand optionally substituted —C₁-C₄ alkyl; and, R⁵⁹ is selected from thegroup consisting of hydrogen and optionally substituted —C₁-C₄ alkyl,optionally substituted —C(O)—C₁-C₄ alkyl, and —C(O)H.
 21. The compoundof claim 1, wherein R⁵⁰ is selected from the group consisting ofP(0)(OH)₂, —P(O)[—OCH₂OC(O)-t-butyl]₂, —P(O)[—OCH(CH₃)OC(O)-t-butyl]₂,—P(O)[—OCH(CH3)OC(O)O-i-propyl]₂, —P(O)[—OCH₂OC(O)O-i-propyl]₂,—P(O)[—N(H)CH(CH₃)C(O)OCH₂CH₃]₂, —P(O)[—N(H)C(CH₃)₂C(O)OCH₂CH₃]₂,—P(O)[—N(H)CH(CH3)C(O)OCH₂CH₃][3,4-methylenedioxyphenyl],—P(O)[—N(H)C(CH3)₂C(O)OCH₂CH₃][3,4-methylenedioxyphenyl],—P(O)[—O—CH₂CH₂S—C(O)CH₃]₂, —P(O)(OH)(OCH₃), —P(O)(OH)(OCH₂CH₃),—P(O)(OH)(CH₃), —P(O)[—OCH(3-chlorophenyl)CH₂CH₂O—],—P(O)[—OCH(pyrid-4-yl)CH₂CH₂O—], —P(O)[—OCH₂OC(O)-t-butyl](OCH₃),—P(O)[—OCH₂OC(O)O-i-propyl](OCH₃), —P(O)[—OCH(CH₃)OC(O)-t-butyl](OCH₃),—P(O)[—OCH(CH₃)OC(O)O-i-propyl](OCH₃), —P(O)[—N(H)CH(CH₃)C(O)OCH₂CH₃](OCH₃), —P(O)[—N(H)CH(CH₃)C(O)OCH₂CH₃](CH₃),—P(O)[—N(H)C(CH₃)₂C(O)OCH₂CH₃](OCH₃),—P(O)[—N(H)C(CH₃)₂C(O)OCH₂CH₃](CH₃), —P(O)[—OCH₂OC(O)-t-butyl](CH₃),—P(O)[—OCH₂OC(O)O-i-propyl](CH₃), —P(O)[—OCH(CH₃)OC(O)-t-butyl](CH₃),and —P(O)[—OCH(CH₃)OC(O)O-i-propyl](CH₃), and —P(O)[—OCH₂OC(O)O-ethyl]₂.22. The compound of claim 1, wherein Y and Y¹ are each independentlyselected from —O— and —NR⁶⁰—; and together R⁵¹ and R⁵¹ are the group

wherein, V is substituted aryl or substituted heteroaryl.
 23. Thecompound of claim 1, wherein G² is CR⁴ or N, or together G² and X areconnected to form a cyclic group containing 5-7 atoms, wherein 0-2 atomsof said cyclic group are heteroatoms and the remaining atoms of saidcyclic group are carbon atoms substituted with alkyl, aryl, cycloalkylor heteroaryl.
 24. The compound of claim 23, wherein G² is CR⁴.
 25. Thecompound of claim 24, wherein R⁴ is H.
 26. The compound of claim 23,wherein together G² and X are connected to form a cyclic groupcontaining 5-7 atoms, wherein 0-2 atoms of said cyclic group areheteroatoms and the remaining atoms of said cyclic group are carbonatoms substituted with alkyl, aryl, cycloalkyl or heteroaryl.
 27. Thecompound of claim 23, wherein G² is N.
 28. The compound of claim 1,wherein: X is selected from the group consisting of alkyloxy andcycloalkyloxy; R² is selected from the group consisting of phenylene-O—,methylene-phenylene-O—, phenylene-methylene-O—, furan-2-yl-5-methylene,thiophen-2-yl-5-methylene, pyridin-diyl-O—, pyrimidin-diyl-O—,pyridazin-diyl-O— and pyrazin-diyl-O—, each optionally substituted withone or two groups independently selected from halogen, CN, CF₃, NR⁵ ₂,—C₁₋₄-alkyl, —S(O)₂R⁵, or —OR⁵, wherein R² is connected to R⁵⁰ by a Cring atom; G¹, G², and G³ are CR⁴ and R⁴ is H; D is selected from thegroup consisting of thiazolyl, 1,3,4-thiadiazolyl, 1,2,4-thiadiazolyl,each optionally substituted with one or two groups selected from thegroup consisting of halogen, CF₃, and optionally substituted C₁₋₄-alkyl;and R⁵⁰ is selected from the group consisting of: P(O)(OH)₂,—P(O)[—OCH₂OC(O)-t-butyl]₂, —P(O)[—OCH(CH₃)OC(O)-t-butyl]₂,—P(O)[—OCH(CH₃)OC(O)O-i-propyl]₂, —P(O)[—OCH₂OC(O)O-i-propyl]₂,—P(O)[—OCH₂OC(O)O-ethyl]₂, —P(O)[—N(H)CH(CH₃)C(O)OCH₂CH₃]₂,—P(O)[—N(H)C(CH₃)₂C(O)OCH₂CH₃]₂, —P(O)[—OCH(3-chlorophenyl)CH₂CH₂O—],—P(O)[—OCH(pyrid-4-yl)CH₂CH₂O—], and —P(O)[—OCH(V)CH₂CH₂O—]; and V isoptionally substituted aryl or optionally substituted heteroaryl. 29.The compound of claim 24, wherein R² is phenylene-O—.
 30. A compound ofclaim 1, wherein: X is selected from the group consisting of alkyloxyand cycloalkyloxy; R² is optionally substitutedmethylene-thiophen-2,5-diyl, phenylene-O—, or thiophen-2-yl-5-methylene,wherein R⁵⁰ is attached to phenylene or thiophenyl; G¹, G², and G³ areCH; D is thiazolyl, optionally substituted with one or two groupsselected from halogen, CF₃, or optionally substituted C₁₋₄-alkyl; R⁵⁰ isselected from the group consisting of —P(O)(OH)₂,—P(O)[—OCH₂OC(O)-t-butyl]₂, —P(O)[—OCH(CH₃)OC(O)-t-butyl]₂,—P(O)[—OCH(CH₃)OC(O)O-i-propyl]₂, —P(O)[—OCH₂OC(O)O-i-propyl]₂,—P(O)[—OCH₂PC(O)O-ethyl]₂, —P(O)[—N(H)CH(CH₃)C(O)OCH₂CH₃]₂,—P(O)[—N(H)C(CH₃)₂C(O)OCH₂CH₃]₂, —P(O)[—OCH(₃-chlorophenyl)CH₂CH₂O—],—P(O)[—OCH(pyrid-4-yl)CH₂CH₂O—], and —P(O)[—OCH(V)CH₂CH₂O—]; and V isoptionally substituted aryl or optionally substituted heteroaryl.
 31. Acompound of general Formula (I),

wherein: X is selected from the group consisting of aryl, heteroaryl,alkyl, cycloalkyl, arylalkyl, aryloxy, heteroaryloxy, alkyloxy,cycloalkyloxy′, and arylalkyloxy; R² is selected from the groupconsisting of alkyl, cycloalkyl, arylalkyl, aryloxy, heteroaryloxy,arylalkyloxy, arylthio, heteroarylthio, cycloalkylthio, andarylalkylthio; D is selected from heteroarylene and arylene, eachoptionally substituted; G¹, G², and G³ are CR⁴ or N; R⁴ is H, halogen,or alkyl; and R⁵⁰ is —R⁶¹-R⁶², and R⁶² is selected from —P(O)(Y²R⁵¹)R¹,or —P(O)(YR⁵¹)Y¹R⁵¹; R⁶¹ is selected from null, arylene, heteroarylene,arylene-alkylene, alkylene-arylene, heteroarylene-alkylene,alkylene-heteroarylene, alkylene, alkenylene, alkynylene,alkylene-Q-alkylene, —CONR⁵²-alkylene, —COO-alkylene, —SO₂NR⁵²-alkylene,arylene-Q-alkylene, alkylene-Q-arylene, heteroarylene-Q-alkylene, oralkylene-Q-heteroarylene, all optionally substituted; Q is selected fromO, S, SO, SO₂, NR⁵³; with the proviso that when D is heteroarylene thenR⁵⁰ is not —(CH₂)n′-Z′—(CH2)m′-PO(OR⁶³)(OR⁶⁴),—(CCH₂)n′-Z′—(CH₂)m′-PO(OR⁶³)R⁶⁵, (CH₂)n′-Z′—(CH₂)m′-0-PO(OR⁶³)R⁶⁵,—(CH₂)n′-Z′—(CH₂)m′-0-PO(R⁶⁵)R⁶⁶, or —(CH₂)n′-Z′—(CH₂)m′-PO—(R⁶⁵)R⁶⁶;R⁶³ and R⁶⁴ are the same or different and are independently selectedfrom the group consisting of hydrogen and alkyl, or R⁶³ and R⁶⁴ can becyclized into a ring; R⁶⁵ and R⁶⁶ are the same or different and areindependently selected from the group consisting of alkyl, aryl,arylalkyl, heteroaryl, and heteroarylalkyl; or R⁶⁵ and R⁶⁶ can becyclized into a ring; or R⁶³ and R⁶⁵ can be cyclized into a ring; Z′ isselected from the group consisting of a bond, alkylene, alkenylene, O,S, and SO₂; m′ is 0, 1, or 2, provided that when Z is 0, S or SO₂, n′ is1 or 2; n′ is 0, 1, or 2; R¹ is selected from the group consisting ofhydrogen, optionally substituted —C₁-C₆-alkyl, —CF₃, —CHF₂, —CH₂F,—CH₂OH, optionally substituted —C₂-C₆ alkenyl, optionally substituted—C₂-C₆ alkynyl, optionally substituted —(CR⁵² ₂)_(n)cycloalkyl,optionally substituted (CR⁵² ₂)_(n)heterocycloalkyl, —(CR⁵²₂)_(k)S(═O)R⁵³, and —(CR⁵² ₂)_(k)S(═O)₂R⁵³; Y, Y¹, and Y² are eachindependently selected from —O— or —NR⁶⁰—; wherein, when Y² is —O— orwhen Y and Y¹ are both —O—, R⁵¹ attached to —O— is independentlyselected from the group consisting of —H, alkyl, optionally substitutedaryl, optionally substituted heterocycloalkyl, optionally substituted—CH₂-heterocycloakyl with a cyclic moiety containing a carbonate orthiocarbonate, optionally substituted -alkylaryl, —C(R⁵²)₂OC(O)NR⁵² ₂,—NR⁵²—C(O)—R⁵³, —C(R⁵²)₂—OC(O)R⁵³, —C(R⁵²)—O—C(O)OR⁵³,—C(R⁵²)₂OC(O)SR⁵³, -alkyl-S—C(O)R⁵³, -alkyl-S—S-alkylhydroxy, and-alkyl-S—S—S-alkylhydroxy; or when Y² is —NR⁶⁰- or when Y and Y¹ areboth —NR⁶⁰—, then R⁵¹ attached to —NR⁶⁰— is independently selected fromthe group consisting of —H, —[C(R⁵²)₂]_(r)—COOR⁵³, —C(R⁵⁴)₂COOR⁵³,—[C(R⁵²)₂]_(r)—C(O)SR⁵³, and -cycloalkylene-COOR⁵³; or when Y is —O— andY¹ is NR⁶⁰, then R⁵¹ attached to —O— is independently selected from —H,alkyl, optionally substituted aryl, optionally substitutedheterocycloalkyl, optionally substituted CH₂-heterocycloakyl wherein thecyclic moiety contains a carbonate or thiocarbonate, optionallysubstituted -alkylaryl, —C(R⁵²)₂OC(O)NR⁵² ₂, —NR⁵²—C(O)—R⁵³,—C(R⁵²)₂—OC(O)R⁵³, —C(R⁵²)₂—O—C(O)OR⁵³, —C(R⁵²)₂OC(O)SR⁵³,-alkyl-S—C(O)R⁵³, -alkyl-S—S-alkylhydroxy, or -alkyl-S—S—S-alkylhydroxy,and R⁵¹ attached to —NR⁶⁰— is independently selected from —H,—[C(R⁵²)₂]_(r)—COOR⁵³, —C(R⁵⁴)₂COOR⁵³, —[C(R⁵²)₂]_(r)—C(O)SR⁵³, or-cycloalkylene-COOR⁵³, wherein if both R⁵¹ are alkyl, at least one ishigher alkyl; or when Y and Y¹ are independently selected from —O— and—NR⁶⁰—, then R⁵¹ and R⁵¹ together form a cyclic group comprising-alkyl-S—S-alkyl-, or R⁵¹ and R⁵¹ together are the group

wherein, V, W, and W′ are independently selected from the groupconsisting of hydrogen, optionally substituted alkyl, optionallysubstituted aralkyl, heterocycloalkyl, aryl, substituted aryl,heteroaryl, substituted heteroaryl, optionally substituted 1-alkenyl,and optionally substituted 1-alkynyl; and Z is —CHR⁵²OH, —CHR⁵²OC(O)R⁵³,—CHR⁵²OC(S)R⁵³, —CHR⁵²OC(S)OR⁵³, —CHR⁵²OC(O)SR⁵³, —CHR⁵²OCO₂R⁵³, —OR⁵²,—SR⁵², —CHR⁵²N₃, —CH₂aryl, —CH(aryl)OH, —CH(CH═CR⁵² ₂)OH, —CH(C≡CR⁵²)OH,—R⁵², —NR⁵² ₂, —OCOR⁵³, —OCO₂R⁵³, —SCOR⁵³, —SCO₂R⁵³, —NHCOR⁵²,—NHCO₂R⁵³, —CH₂NHaryl, —(CH₂)_(r)—OR⁵², or —(CH₂)_(r)—SR⁵²; or W and W′are as defined above and together V and Z are connected via anadditional 3-5 atoms to form a cyclic group containing 5-7 atoms,wherein 0-1 atoms are heteroatoms and the remaining atoms are carbon; orW′ and Z are as defined above and together V and Ware connected via anadditional 3 carbon atoms to form an optionally substituted cyclic groupcontaining 6 carbon atoms or carbon substituted by hydrogen andsubstituted with one substituent selected from hydroxy, acyloxy,alkoxycarbonyloxy, alkylthiocarbonyloxy, or aryloxycarbonyloxy which isattached to one of said carbon atoms that is three atoms from a Yattached to the phosphorus; or V and W′ are as defined above andtogether Z and W are connected via an additional 3-5 atoms to form acyclic group, wherein 0-1 atoms are heteroatoms and the remaining atomsare carbon or carbon substituted by hydrogen, and V must be aryl,substituted aryl, heteroaryl, or substituted heteroaryl; or V and Z areas defined above and together W and W′ are connected via an additional2-5 atoms to form a cyclic group, wherein 0-2 atoms are heteroatoms andthe remaining atoms are carbon, where V must be aryl, substituted aryl,heteroaryl, or substituted heteroaryl; R⁵² is R⁵³ or —H; R⁵³ is alkyl,aryl, heterocycloalkyl, or aralkyl; R⁵⁴ is independently selected from—H or alkyl, or together R⁵⁴ and R⁵⁴ form a cycloalkylene group; R⁶⁰ is—H, lower alkyl, acyloxyalkyl, alkoxycarbonyloxyalkyl, lower acyl,C₁₋₆-perfluoroalkyl, or NH(CR⁵⁵R⁵⁵)_(f)CH₃; r is an integer 2 or 3; f isan integer 0, 1, or 2; wherein, V, Z, W, W′ are not all —H, and when Zis —R⁵², then at least one of V, W, and W′ is not —H, alkyl, aralkyl, orheterocycloalkyl; and pharmaceutically acceptable salt thereof.
 32. Apharmaceutical composition comprising a compound of claim 1 and apharmaceutically acceptable excipient.
 33. A pharmaceutical compositioncomprising a compound of claim 31 and a pharmaceutically acceptableexcipient.
 34. A method of treating a disease or condition selected fromthe group consisting of Type 1 diabetes, Type 2 diabetes, impairedglucose tolerance, insulin resistance, hyperglycemia, acceleratedgluconeogenesis, hyperinsulinemia, excessive hepatic glucose output, andMetabolic Syndrome X, said method comprising the step of administeringto an animal a therapeutically effective amount of a compound of claim1, a composition thereof, or a pharmaceutically acceptable salt thereof.35. A method of treating a disease or condition selected from the groupconsisting of Type 1 diabetes, Type 2 diabetes, impaired glucosetolerance, insulin resistance, hyperglycemia, acceleratedgluconeogenesis, hyperinsulinemia, excessive hepatic glucose output, andMetabolic Syndrome X, said method comprising the step of administeringto an animal a therapeutically effective amount of a compound of claim31, a composition thereof, or a pharmaceutically acceptable saltthereof.